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1.  Perinatal psychosis in mothers with a history of major depressive disorder 
Archives of women's mental health  2015;19(2):253-258.
Purpose
While women with a history of major depressive disorder (MDD) have higher chances for postpartum depressive and manic episodes, little is known about their chance for postpartum psychosis (PPP). We prospectively assessed the frequency of perinatal psychotic symptoms among primiparous women with a history of MDD only (structured clinical interview was used to exclude women with pre-existing histories of mania or psychosis), and explored whether sex of the baby influenced these symptoms.
Methods
The presence of symptoms of psychosis was defined using previously established cutoff scores on five key items from the Positive and Negative Syndrome Scale (PANSS), which was administered during pregnancy, at 1 week, 1 month, and 3 months postpartum.
Results
Fourteen of 60 women (23%) scored above threshold for psychosis at one or more time-points, with six experiencing postpartum onset. There was a non-significant trend (p = 0.073) towards higher frequency of these symptoms among mothers of girls.
Conclusions
If controlled studies using diagnostic interviews confirm that psychotic symptoms are relatively common among women with MDD, monitoring for psychosis during the perinatal period may be indicated in this population. The potential effect of sex of the baby on mothers’ chance for PPP requires further study.
doi:10.1007/s00737-015-0561-9
PMCID: PMC4739833  PMID: 26260036 CAMSID: cams5165
depression; pregnancy; postpartum; mental illness; psychosis
2.  Mania and depression in the perinatal period among women with a history of major depressive disorders 
Archives of women's mental health  2014;17(2):137-143.
Background
Women with a history of major depressive disorder (MDD) have increased risks for postpartum depression, but less is known about postpartum mania in this population.
Objectives
To prospectively determine the frequency with which mania occurs in the postpartum among women who have a history of MDD, and to explore temporal relationships between onset of mania/hypomania and depression.
Methods
We administered the Structured Clinical Interview for DSM IV disorders (SCID) to pregnant women with a self-reported history of MDD to confirm diagnosis and exclude women with any history of mania/hypomania. Participants completed the Edinburgh Postnatal Depression Scale (EPDS) and Altman Self-Rated Mania scale (ASRM): once during the pregnancy (~26 weeks), and one week, one month, and three months postpartum.
Results
Among women (N=107) with a SCID-confirmed diagnosis of MDD, 34.6% (n=37) experienced mania/hypomania (defined by an ASRM score of ≥6) at ≥1 timepoint during the postpartum: and for just over half (20/37, 54%), onset was during the postpartum. The highest frequency of mania/hypomania (26.4%, n=26) was at one week postpartum. Women who experienced mania/hypomania at one week postpartum had significantly more symptoms of mania/hypomania later in the postpartum.
Conclusion
A substantive proportion of women with a history of MDD may experience first onset of mania/hypomania symptoms in the early postpartum, others may experience first onset during pregnancy. Taken with other recent data, these findings suggest a possible rationale for screening women with a history of MDD for mania/hypomania during the early postpartum period, but issues with screening instruments are discussed.
doi:10.1007/s00737-013-0408-1
PMCID: PMC3961475  PMID: 24402681 CAMSID: cams3835
postpartum; depression; mania; postnatal; hypomania; women
3.  Impact of increased risk for fetal aneuploidy on maternal mood: a prospective longitudinal study 
Introduction
Our goal was to prospectively compare the trajectories of depression symptoms through pregnancy and the postpartum between women who received normal prenatal screening results and those whose results indicated an increased risk for fetal aneuploidy.
Material and Methods
Women completed the Edinburgh Postnatal Depression Scale (EPDS) at four-week intervals between <26 weeks gestation and three months postpartum. We categorized women into four groups: 1) negative serum screening and ultrasound results (SS−/US−, n=103), 2) positive serum screening/negative ultrasound results (SS+/US−, n=42), 3) negative serum screening/positive ultrasound results (SS−/US+, n=19), or 4) positive serum screening and ultrasound results (SS+/US+, n=13), and compared EPDS scores between groups using Poisson regression.
Results
Women who received any positive prenatal screening result had significantly higher EPDS scores during pregnancy than SS−/US− women (p = 0.002), with SS−/US+ women having the highest scores. During the postpartum, any positive screening test result was only marginally significantly associated with EPDS scores (p=0.06), but women in the SS−/US+ group had significantly higher scores than women in the SS−/US− group (p = 0.05).
Conclusion
Our data suggest that different types of prenatal screening tests may have different effects on women’s moods, and that depression symptoms persist for women who have soft markers identified on ultrasound.
doi:10.1111/aogs.12951
PMCID: PMC5226846  PMID: 27461056 CAMSID: cams6464
Prenatal screening; soft markers; depression; mood; postpartum; pregnancy
4.  A pilot randomized clinical trial evaluating the impact of genetic counseling for serious mental illnesses 
The Journal of clinical psychiatry  2016;77(2):e190-e198.
Objective
The serious mental illnesses schizophrenia, schizoaffective disorder, and bipolar disorder are complex conditions affecting 1–4% of the population. Individuals with serious mental illnesses express interest in genetic counseling; an intervention showing promise for increasing patient knowledge and adaptation. This trial aimed to evaluate the effects of genetic counseling for people with serious mental illnesses as compared to an educational intervention or waitlist.
Methods
A pilot three-arm (each n=40; genetic counseling, a control intervention involving an educational booklet, or waitlist), parallel group, randomized clinical trial was conducted from September 2008–November 2011 in Vancouver, Canada. Participants with schizophrenia, bipolar disorder, or schizoaffective disorder (DSM-IV) completed outcome measures assessing knowledge, risk perception, internalized stigma, and perceived control over illness at baseline and one-month follow-up. The Brief Symptom Inventory was administered to control for current symptoms. Analyses included linear mixed effects models and chi-squared tests.
Results
Knowledge increased for genetic counseling/educational booklet compared to waitlist at follow-up (LRT=19.33, df=1, Holm-adjusted p=0.0003, R2LMM(m)=0.17). Risk perception accuracy increased at follow-up for genetic counseling compared to waitlist (Yates’ continuity corrected χ2=9.1, df=1, Bonferroni p=0.003) and educational booklet (Yates’ continuity corrected χ2=8.2, df=1, Bonferroni p=0.004). There were no significant differences between groups for stigma or perceived control scores.
Conclusions
Genetic counseling and the educational booklet improved knowledge; and genetic counseling, but not the educational booklet, improved risk perception accuracy for this population. The impact of genetic counseling on internalized stigma and perceived control is worth further investigation. Genetic counseling should be considered for patients with serious mental illnesses.
Trial registration
clinicaltrials.gov identifier: NCT00713804; http://clinicaltrials.gov/ct2/show/NCT00713804?term=genetic+counseling&rank=4
doi:10.4088/JCP.14m09710
PMCID: PMC4864025  PMID: 26930535 CAMSID: cams5452
mental illness; genetic counseling; psychiatric disorders; bipolar disorder; schizophrenia; schizoaffective disorder; internalized stigma; perceived control; knowledge; risk perception; randomized clinical trial
5.  A “cure” for Down syndrome: What do parents want? 
Clinical genetics  2014;86(4):310-317.
Recent advancements in molecular genetics raise the possibility that therapeutics or a “cure” for Down syndrome (DS) may become available. However, there are no data regarding how parents of children with DS perceive the possibility of mitigating specific manifestations such as the intellectual disability (ID) associated with DS, or curing the condition entirely. To explore these issues, we distributed a questionnaire to members of the Lower Mainland Down Syndrome Society in British Columbia, Canada. Questionnaires were completed by 101 parents (response rate=41%). A majority (61%) viewed the possibility of reversing ID in DS positively, but only 41% said that they would “cure” their child of DS if it were possible. Twenty-seven percent of respondents said they would not “cure” their child, and 32% were unsure if they would “cure” their child. The most commonly cited motivation for opting for a “cure” was to increase their child’s independence. However, parental attitudes’ towards a “cure” for DS were complex, affected by ethical issues, perceived societal values, and pragmatic factors such as the age of the individual and long-term care-giving burden. These findings could be used by healthcare professionals supporting families who include a member with DS and to direct future research.
doi:10.1111/cge.12364
PMCID: PMC4055389  PMID: 24548046 CAMSID: cams4213
Down syndrome; intellectual disability; therapeutics; cure; attitudes; parents
6.  “Nothing is absolute in life”: Understanding uncertainty in the context of psychiatric genetic counseling from the perspective of those with serious mental illness 
Journal of genetic counseling  2013;22(5):625-632.
No genetic tests are currently clinically available for serious mental illnesses such as schizophrenia and bipolar disorder. Rather, the full spectrum of genetic variants that confer susceptibility remain unknown, and estimates of probability of condition recurrence typically have the form of ranges rather than single absolute numbers. Genetic counselors have been shown to feel that the information that can be provided for patients with serious mental illness could be more confusing than helpful. However, how those with serious mental illness perceive this uncertainty remains unknown. So, to investigate this, individuals with serious mental illness participated in a psychiatric genetic counseling (GC) session and responded to a single open ended question about their reactions towards the uncertainty that they encountered in their GC session immediately and one month post-counseling (from which themes were identified), and completed the Genetic Counseling Satisfaction Scale immediately post-session (descriptive statistics applied). While some of the 37 participants were disappointed with the uncertainty, twice as many were unconcerned. Overall, responses from immediately and one month after GC were very similar; participants were very satisfied with, and found value in GC despite uncertainty, and four approaches to coping with uncertainty emerged. Ultimately, these findings offer insight into providing GC for those with serious mental illness, and potentially could be applied to other areas of GC where uncertainty lies, with downstream impact on GC practice and future research.
doi:10.1007/s10897-013-9594-2
PMCID: PMC3776779  PMID: 23604904 CAMSID: cams3140
Mental illness; Genetic counseling; Uncertainty; Psychiatric disorders; Bipolar disorder; Schizophrenia; Schizoaffective disorder; Satisfaction
7.  Red blood cell folate levels in pregnant women with a history of mood disorders: a case series 
Objective
Maternal folate supplementation reduces offspring risk for neural tube defects (NTDs) and other congenital abnormalities. Maternal red blood cell (RBC) folate concentrations of >906nmol/L have been associated with the lowest risk of having an NTD affected pregnancy. Mood disorders (e.g. depression, bipolar disorder) are common among women and can be associated with folate deficiency. Thus, pregnant women with histories of mood disorders may be prone to RBC folate levels insufficient to provide optimal protection against NTDs. While previous studies have assessed RBC folate concentrations in pregnant women from the general population, none have looked specifically at a group of pregnant women who have a history of a mood disorder.
Methods
We collected data about RBC folate concentrations and folic acid supplement intake during early pregnancy (<161days gestation) from n=24 women with histories of mood disorders. We also collected information about offspring congenital abnormalities and birthweight.
Results
Among women with histories of mood disorders, the mean RBC folate concentration was 674 nmol/L (range: 362 –1105nmol/L). Only 12.5% (n=3) of the women had an RBC folate concentrations >906nmol/L, despite all participants reporting current daily use of folic acid supplements. Data regarding offspring were available for 22 women: birthweights ranged from 2296g to 4819g, and congenital abnormalities were identified in two (hypoplastic left heart, annular pancreas).
Conclusion
Data from this exploratory case series suggest a need for future larger scale controlled studies investigating RBC folate concentrations in early pregnancy and offspring outcomes among women with and without histories of mood disorders.
doi:10.1002/bdra.23144
PMCID: PMC3951991  PMID: 23760977 CAMSID: cams3096
folic acid; folate; pregnancy; mood disorders; depression; birth defects; congenital abnormalities
8.  Beyond Trisomy 21: Additional Chromosomal Anomalies Detected through Routine Aneuploidy Screening 
Journal of Clinical Medicine  2014;3(2):388-415.
Prenatal screening is often misconstrued by patients as screening for trisomy 21 alone; however, other chromosomal anomalies are often detected. This study aimed to systematically review the literature and use diagnostic meta-analysis to derive pooled detection and false positive rates for aneuploidies other than trisomy 21 with different prenatal screening tests. Non-invasive prenatal testing had the highest detection (DR) and lowest false positive (FPR) rates for trisomy 13 (DR: 90.3%; FPR: 0.2%), trisomy 18 (DR: 98.1%; FPR: 0.2%), and 45,X (DR: 92.2%; FPR: 0.1%); however, most estimates came from high-risk samples. The first trimester combined test also had high DRs for all conditions studied (trisomy 13 DR: 83.1%; FPR: 4.4%; trisomy 18 DR: 91.9%; FPR: 3.5%; 45,X DR: 70.1%; FPR: 5.4%; triploidy DR: 100%; FPR: 6.3%). Second trimester triple screening had the lowest DRs and highest FPRs for all conditions (trisomy 13 DR: 43.9%; FPR: 8.1%; trisomy 18 DR: 70.5%; FPR: 3.3%; 45,X DR: 77.2%; FPR: 9.3%). Prenatal screening tests differ in their ability to accurately detect chromosomal anomalies. Patients should be counseled about the ability of prenatal screening to detect anomalies other than trisomy 21 prior to undergoing screening.
doi:10.3390/jcm3020388
PMCID: PMC4449689  PMID: 26237381
aneuploidy; prenatal; maternal serum; ultrasound; non-invasive testing; sensitivity; specificity
9.  Depression During Pregnancy: The Potential Impact of Increased Risk for Fetal Aneuploidy on Maternal Mood 
Clinical genetics  2008;75(1):30-36.
Introduction
Depression during pregnancy can have serious consequences for families. Indications of fetal aneuploidy can induce maternal stress, a risk factor for depression. Few studies have assessed symptoms of depression in pregnant women soon after they receive results indicating increased risk for fetal aneuploidy.
Purpose
We compared symptoms of depression in women who had increased risks for fetal aneuploidy with two other groups of pregnant women at similar gestational ages: Controls, and women taking antidepressant medication (MEDS).
Methods
81 women attending the BC Medical Genetics Programme (MG) regarding positive maternal serum screens or ultrasound soft marker findings completed the Edinburgh Postnatal Depression Scale (EPDS). Control (n=41) and MEDS (n=41) groups were recruited from the community or the BC Reproductive Mental Health program. A threshold score of 12 on the EPDS was used to calculate percentages of women likely to be depressed. Mean EPDS scores were compared using ANOVA, followed by post-hoc tests.
Results
In the Control, MG, and MEDS groups, 2.4%, 35%, and 52.4% of women, respectively, scored above 12. Mean EPDS score was significantly higher in the MG group than in the Control group (p<.0001).
Conclusions
These results suggest a place for depression screening in prenatal genetic counselling.
doi:10.1111/j.1399-0004.2008.01056.x
PMCID: PMC3965564  PMID: 18637940 CAMSID: cams3083
DEPRESSION; FETAL ANEUPLOIDY; GENETIC COUNSELLING; MATERNAL SERUM SCREEN; MOOD; PREGNANCY; PRENATAL; ULTRASOUND SOFT MARKER
10.  Prenatal testing for Down syndrome: The perspectives of parents of individuals with Down syndrome 
This exploratory, descriptive study examined the views and opinions of parents of individuals with Down syndrome (DS) related to prenatal testing for DS and the use of age-based criteria to determine eligibility for this testing. This survey-based study was designed in collaboration with parents of individuals with DS and the British Columbia-based Lower Mainland Down Syndrome Society (LMDSS). The survey was a 26-item, self-report questionnaire, which was distributed by the LMDSS. Out of the 246 potentially eligible individuals that were mailed surveys, 101 participants returned their completed surveys. The availability of prenatal screening and diagnostic testing for DS was perceived positively by 55.1% and 64.7% of parents, respectively. More than half (60.2%) of participants felt that prenatal diagnostic testing for DS should be available to all pregnant women, regardless of age. In this study, views of Canadian parents of individuals with DS aligned with the prenatal testing policy recently adopted in the USA (whereby any woman, regardless of age or risk factors, can opt for prenatal diagnostic testing) rather than with new Canadian policy (whereby the age for automatic eligibility for diagnostic testing had increased from 35 to 40 years old and more recently is no longer offered on the basis of age-related risks, but on the basis of other risk factors).
doi:10.1002/ajmg.a.35238
PMCID: PMC3958964  PMID: 22354662 CAMSID: cams3092
Down syndrome; prenatal testing; prenatal screening; parent’s attitudes; prenatal diagnosis; policy recommendations; guidelines
11.  Genetic counseling for schizophrenia: a review of referrals to a provincial medical genetics program from 1968–2007 
Purpose
Recent studies have shown that individuals with schizophrenia and their family members are interested in genetic counseling, but few have received this service. We conducted an exploratory, retrospective study to describe (a) the population of individuals who were referred to the provincial program for genetic counseling for a primary indication of schizophrenia, and (b) trends in number of referrals between 1968 and 2007.
Methods
Referrals for a primary indication of schizophrenia were identified through the provincial program database. Charts were reviewed and the following information was recorded: discipline of referring physician, demographics, psychiatric diagnosis, referred individual’s and partner’s (if applicable) family history, and any current pregnancy history. Data were characterized using descriptive statistics.
Results
Between 1968 and 2007, 288 referrals were made for a primary indication of schizophrenia. Most referrals were made: (a) for individuals who had a first-degree family member with schizophrenia, rather than for affected individuals, (b) for preconception counseling, and (c) by family physicians (69%), with only 2% by psychiatrists.
Conclusions
In British Columbia, individuals affected with schizophrenia and their family members are rarely referred for psychiatric genetic counseling. There is a need to identify barriers to psychiatric genetic counseling and develop strategies to improve access.
doi:10.1002/ajmg.a.33193
PMCID: PMC3958978  PMID: 20034078 CAMSID: cams3084
Family History; Genetic Counseling; Psychiatric; Referrals; Schizophrenia
12.  Descriptive and numeric estimation of risk for psychotic disorders among affected individuals and relatives: Implications for clinical practice 
Psychiatry research  2012;196(1):52-56.
Studies show that individuals with psychotic illnesses and their families want information about psychosis risks for other relatives. However, deriving accurate numeric probabilities for psychosis risk is challenging, and people have difficulty interpreting probabilistic information, thus some have suggested that clinicians should use risk descriptors, such as ‘moderate’ or ‘quite high’, rather than numbers. Little is known about how individuals with psychosis and their family members use quantitative and qualitative descriptors of risk in the specific context of chance for an individual to develop psychosis. We explored numeric and descriptive estimations of psychosis risk among individuals with psychotic disorders and unaffected first-degree relatives. In an online survey, respondents numerically and descriptively estimated risk for an individual to develop psychosis in scenarios where they had: A) no affected family members; and B) an affected sibling. 219 affected individuals and 211 first-degree relatives participated. Affected individuals estimated significantly higher risks than relatives. Participants attributed all descriptors between “very low” and “very high” to probabilities of 1%, 10%, 25% and 50%+. For a given numeric probability, different risk descriptors were attributed in different scenarios. Clinically, brief interventions around risk (using either probabilities or descriptors alone) are vulnerable to miscommunication and potentially profoundly negative consequences –interventions around risk are best suited to in-depth discussion.
doi:10.1016/j.psychres.2012.02.005
PMCID: PMC3723521  PMID: 22421074 CAMSID: cams3094
risk perception; genetic counseling; probability; recurrence risks; schizophrenia; schizoaffective disorder; bipolar disorder; family members; psychosis; psychotic disorders
13.  What is a “balanced” description? Insight from parents of individuals with Down syndrome 
Journal of genetic counseling  2011;21(1):35-44.
Introduction
Genetic counselors and parents of individuals with Down syndrome (DS) agree that descriptions of DS in prenatal settings should be “balanced.” However, there is no consensus regarding what constitutes a balanced description of DS.
Methods
A survey was designed in collaboration with, and sent to the membership of, the British Columbia based Lower Mainland Down Syndrome Society (N=260). Respondents were asked how they would describe DS to a couple who have just received a prenatal diagnosis of the condition. We rated the descriptions provided for positivity/negativity.
Results
Completed surveys were returned by 101 members, the majority of whom were Caucasian (87%) and female (79%). Participants’ descriptions of DS ranged from entirely positive (n = 5; 10%) to entirely negative (n = 4; 7%) in nature.
Conclusions
Deriving a description of DS that would broadly be perceived as “balanced” may be impossible. Instead, it may be more important to explore the range of possibilities regarding the family experience of raising a child with DS using nonjudgmental terminology, and to help families evaluate these possibilities in the context of their own values, coping strategies, and support networks.
doi:10.1007/s10897-011-9417-2
PMCID: PMC3706329  PMID: 22183831 CAMSID: cams3091
DOWN SYNDROME; BALANCED DESCRIPTION; BALANCED INFORMATION; PARENTS; OPINIONS; PRENATAL SCREENING; PRENATAL DIAGNOSIS; GENETIC COUNSELING
14.  31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two 
Ager, Casey | Reilley, Matthew | Nicholas, Courtney | Bartkowiak, Todd | Jaiswal, Ashvin | Curran, Michael | Albershardt, Tina C. | Bajaj, Anshika | Archer, Jacob F. | Reeves, Rebecca S. | Ngo, Lisa Y. | Berglund, Peter | ter Meulen, Jan | Denis, Caroline | Ghadially, Hormas | Arnoux, Thomas | Chanuc, Fabien | Fuseri, Nicolas | Wilkinson, Robert W. | Wagtmann, Nicolai | Morel, Yannis | Andre, Pascale | Atkins, Michael B. | Carlino, Matteo S. | Ribas, Antoni | Thompson, John A. | Choueiri, Toni K. | Hodi, F. Stephen | Hwu, Wen-Jen | McDermott, David F. | Atkinson, Victoria | Cebon, Jonathan S. | Fitzharris, Bernie | Jameson, Michael B. | McNeil, Catriona | Hill, Andrew G. | Mangin, Eric | Ahamadi, Malidi | van Vugt, Marianne | van Zutphen, Mariëlle | Ibrahim, Nageatte | Long, Georgina V. | Gartrell, Robyn | Blake, Zoe | Simoes, Ines | Fu, Yichun | Saito, Takuro | Qian, Yingzhi | Lu, Yan | Saenger, Yvonne M. | Budhu, Sadna | De Henau, Olivier | Zappasodi, Roberta | Schlunegger, Kyle | Freimark, Bruce | Hutchins, Jeff | Barker, Christopher A. | Wolchok, Jedd D. | Merghoub, Taha | Burova, Elena | Allbritton, Omaira | Hong, Peter | Dai, Jie | Pei, Jerry | Liu, Matt | Kantrowitz, Joel | Lai, Venus | Poueymirou, William | MacDonald, Douglas | Ioffe, Ella | Mohrs, Markus | Olson, William | Thurston, Gavin | Capasso, Cristian | Frascaro, Federica | Carpi, Sara | Tähtinen, Siri | Feola, Sara | Fusciello, Manlio | Peltonen, Karita | Martins, Beatriz | Sjöberg, Madeleine | Pesonen, Sari | Ranki, Tuuli | Kyruk, Lukasz | Ylösmäki, Erkko | Cerullo, Vincenzo | Cerignoli, Fabio | Xi, Biao | Guenther, Garret | Yu, Naichen | Muir, Lincoln | Zhao, Leyna | Abassi, Yama | Cervera-Carrascón, Víctor | Siurala, Mikko | Santos, João | Havunen, Riikka | Parviainen, Suvi | Hemminki, Akseli | Dalgleish, Angus | Mudan, Satvinder | DeBenedette, Mark | Plachco, Ana | Gamble, Alicia | Grogan, Elizabeth W. | Krisko, John | Tcherepanova, Irina | Nicolette, Charles | Dhupkar, Pooja | Yu, Ling | Kleinerman, Eugenie S. | Gordon, Nancy | Grenga, Italia | Lepone, Lauren | Gameiro, Sofia | Knudson, Karin M. | Fantini, Massimo | Tsang, Kwong | Hodge, James | Donahue, Renee | Schlom, Jeffrey | Evans, Elizabeth | Bussler, Holm | Mallow, Crystal | Reilly, Christine | Torno, Sebold | Scrivens, Maria | Foster, Cathie | Howell, Alan | Balch, Leslie | Knapp, Alyssa | Leonard, John E. | Paris, Mark | Fisher, Terry | Hu-Lieskovan, Siwen | Ribas, Antoni | Smith, Ernest | Zauderer, Maurice | Fogler, William | Franklin, Marilyn | Thayer, Matt | Saims, Dan | Magnani, John L. | Gong, Jian | Gray, Michael | Hutchins, Jeff | Freimark, Bruce | Fromm, George | de Silva, Suresh | Giffin, Louise | Xu, Xin | Rose, Jason | Schreiber, Taylor H. | Fantini, Massimo | Gameiro, Sofia R. | Knudson, Karin M. | Clavijo, Paul E. | Allen, Clint T. | Donahue, Renee | Lepone, Lauren | Grenga, Italia | Hodge, James W. | Tsang, Kwong Y. | Schlom, Jeffrey | Gray, Michael | Gong, Jian | Hutchins, Jeff | Freimark, Bruce | Grogan, Jane | Manieri, Nicholas | Chiang, Eugene | Caplazi, Patrick | Yadav, Mahesh | Hagner, Patrick | Chiu, Hsiling | Waldman, Michelle | Klippel, Anke | Thakurta, Anjan | Pourdehnad, Michael | Gandhi, Anita | Henrich, Ian | Quick, Laura | Young, Rob | Chou, Margaret | Hotson, Andrew | Willingham, Stephen | Ho, Po | Choy, Carmen | Laport, Ginna | McCaffery, Ian | Miller, Richard | Tipton, Kimberly A. | Wong, Kenneth R. | Singson, Victoria | Wong, Chihunt | Chan, Chanty | Huang, Yuanhiu | Liu, Shouchun | Richardson, Jennifer H. | Kavanaugh, W. Michael | West, James | Irving, Bryan A. | Tipton, Kimberly A. | Wong, Kenneth R. | Singson, Victoria | Wong, Chihunt | Chan, Chanty | Huang, Yuanhiu | Liu, Shouchun | Richardson, Jennifer H. | Kavanaugh, W. Michael | West, James | Irving, Bryan A. | Jaini, Ritika | Loya, Matthew | Eng, Charis | Johnson, Melissa L. | Adjei, Alex A. | Opyrchal, Mateusz | Ramalingam, Suresh | Janne, Pasi A. | Dominguez, George | Gabrilovich, Dmitry | de Leon, Laura | Hasapidis, Jeannette | Diede, Scott J. | Ordentlich, Peter | Cruickshank, Scott | Meyers, Michael L. | Hellmann, Matthew D. | Kalinski, Pawel | Zureikat, Amer | Edwards, Robert | Muthuswamy, Ravi | Obermajer, Nataša | Urban, Julie | Butterfield, Lisa H. | Gooding, William | Zeh, Herbert | Bartlett, David | Zubkova, Olga | Agapova, Larissa | Kapralova, Marina | Krasovskaia, Liudmila | Ovsepyan, Armen | Lykov, Maxim | Eremeev, Artem | Bokovanov, Vladimir | Grigoryeva, Olga | Karpov, Andrey | Ruchko, Sergey | Nicolette, Charles | Shuster, Alexandr | Khalil, Danny N. | Campesato, Luis Felipe | Li, Yanyun | Merghoub, Taha | Wolchok, Jedd D. | Lazorchak, Adam S. | Patterson, Troy D. | Ding, Yueyun | Sasikumar, Pottayil | Sudarshan, Naremaddepalli | Gowda, Nagaraj | Ramachandra, Raghuveer | Samiulla, Dodheri | Giri, Sanjeev | Eswarappa, Rajesh | Ramachandra, Murali | Tuck, David | Wyant, Timothy | Leshem, Jasmin | Liu, Xiu-fen | Bera, Tapan | Terabe, Masaki | Bossenmaier, Birgit | Niederfellner, Gerhard | Reiter, Yoram | Pastan, Ira | Xia, Leiming | Xia, Yang | Hu, Yangyang | Wang, Yi | Bao, Yangyi | Dai, Fu | Huang, Shiang | Hurt, Elaine | Hollingsworth, Robert E. | Lum, Lawrence G. | Chang, Alfred E. | Wicha, Max S. | Li, Qiao | Mace, Thomas | Makhijani, Neil | Talbert, Erin | Young, Gregory | Guttridge, Denis | Conwell, Darwin | Lesinski, Gregory B. | Gonzales, Rodney JM Macedo | Huffman, Austin P. | Wang, Ximi K. | Reshef, Ran | MacKinnon, Andy | Chen, Jason | Gross, Matt | Marguier, Gisele | Shwonek, Peter | Sotirovska, Natalija | Steggerda, Susanne | Parlati, Francesco | Makkouk, Amani | Bennett, Mark K. | Chen, Jason | Emberley, Ethan | Gross, Matt | Huang, Tony | Li, Weiqun | MacKinnon, Andy | Marguier, Gisele | Neou, Silinda | Pan, Alison | Zhang, Jing | Zhang, Winter | Parlati, Francesco | Marshall, Netonia | Marron, Thomas U. | Agudo, Judith | Brown, Brian | Brody, Joshua | McQuinn, Christopher | Mace, Thomas | Farren, Matthew | Komar, Hannah | Shakya, Reena | Young, Gregory | Ludwug, Thomas | Lesinski, Gregory B. | Morillon, Y. Maurice | Hammond, Scott A. | Schlom, Jeffrey | Greiner, John W. | Nath, Pulak R. | Schwartz, Anthony L. | Maric, Dragan | Roberts, David D. | Obermajer, Nataša | Bartlett, David | Kalinski, Pawel | Naing, Aung | Papadopoulos, Kyriakos P. | Autio, Karen A. | Wong, Deborah J. | Patel, Manish | Falchook, Gerald | Pant, Shubham | Ott, Patrick A. | Whiteside, Melinda | Patnaik, Amita | Mumm, John | Janku, Filip | Chan, Ivan | Bauer, Todd | Colen, Rivka | VanVlasselaer, Peter | Brown, Gail L. | Tannir, Nizar M. | Oft, Martin | Infante, Jeffrey | Lipson, Evan | Gopal, Ajay | Neelapu, Sattva S. | Armand, Philippe | Spurgeon, Stephen | Leonard, John P. | Hodi, F. Stephen | Sanborn, Rachel E. | Melero, Ignacio | Gajewski, Thomas F. | Maurer, Matthew | Perna, Serena | Gutierrez, Andres A. | Clynes, Raphael | Mitra, Priyam | Suryawanshi, Satyendra | Gladstone, Douglas | Callahan, Margaret K. | Crooks, James | Brown, Sheila | Gauthier, Audrey | de Boisferon, Marc Hillairet | MacDonald, Andrew | Brunet, Laura Rosa | Rothwell, William T. | Bell, Peter | Wilson, James M. | Sato-Kaneko, Fumi | Yao, Shiyin | Zhang, Shannon S. | Carson, Dennis A. | Guiducci, Cristina | Coffman, Robert L. | Kitaura, Kazutaka | Matsutani, Takaji | Suzuki, Ryuji | Hayashi, Tomoko | Cohen, Ezra E. W. | Schaer, David | Li, Yanxia | Dobkin, Julie | Amatulli, Michael | Hall, Gerald | Doman, Thompson | Manro, Jason | Dorsey, Frank Charles | Sams, Lillian | Holmgaard, Rikke | Persaud, Krishnadatt | Ludwig, Dale | Surguladze, David | Kauh, John S. | Novosiadly, Ruslan | Kalos, Michael | Driscoll, Kyla | Pandha, Hardev | Ralph, Christy | Harrington, Kevin | Curti, Brendan | Sanborn, Rachel E. | Akerley, Wallace | Gupta, Sumati | Melcher, Alan | Mansfield, David | Kaufman, David R. | Schmidt, Emmett | Grose, Mark | Davies, Bronwyn | Karpathy, Roberta | Shafren, Darren | Shamalov, Katerina | Cohen, Cyrille | Sharma, Naveen | Allison, James | Shekarian, Tala | Valsesia-Wittmann, Sandrine | Caux, Christophe | Marabelle, Aurelien | Slomovitz, Brian M. | Moore, Kathleen M. | Youssoufian, Hagop | Posner, Marshall | Tewary, Poonam | Brooks, Alan D. | Xu, Ya-Ming | Wijeratne, Kithsiri | Gunatilaka, Leslie A. A. | Sayers, Thomas J. | Vasilakos, John P. | Alston, Tesha | Dovedi, Simon | Elvecrog, James | Grigsby, Iwen | Herbst, Ronald | Johnson, Karen | Moeckly, Craig | Mullins, Stefanie | Siebenaler, Kristen | SternJohn, Julius | Tilahun, Ashenafi | Tomai, Mark A. | Vogel, Katharina | Wilkinson, Robert W. | Vietsch, Eveline E. | Wellstein, Anton | Wythes, Martin | Crosignani, Stefano | Tumang, Joseph | Alekar, Shilpa | Bingham, Patrick | Cauwenberghs, Sandra | Chaplin, Jenny | Dalvie, Deepak | Denies, Sofie | De Maeseneire, Coraline | Feng, JunLi | Frederix, Kim | Greasley, Samantha | Guo, Jie | Hardwick, James | Kaiser, Stephen | Jessen, Katti | Kindt, Erick | Letellier, Marie-Claire | Li, Wenlin | Maegley, Karen | Marillier, Reece | Miller, Nichol | Murray, Brion | Pirson, Romain | Preillon, Julie | Rabolli, Virginie | Ray, Chad | Ryan, Kevin | Scales, Stephanie | Srirangam, Jay | Solowiej, Jim | Stewart, Al | Streiner, Nicole | Torti, Vince | Tsaparikos, Konstantinos | Zheng, Xianxian | Driessens, Gregory | Gomes, Bruno | Kraus, Manfred | Xu, Chunxiao | Zhang, Yanping | Kradjian, Giorgio | Qin, Guozhong | Qi, Jin | Xu, Xiaomei | Marelli, Bo | Yu, Huakui | Guzman, Wilson | Tighe, Rober | Salazar, Rachel | Lo, Kin-Ming | English, Jessie | Radvanyi, Laszlo | Lan, Yan | Zappasodi, Roberta | Budhu, Sadna | Hellmann, Matthew D. | Postow, Michael | Senbabaoglu, Yasin | Gasmi, Billel | Zhong, Hong | Li, Yanyun | Liu, Cailian | Hirschhorhn-Cymerman, Daniel | Wolchok, Jedd D. | Merghoub, Taha | Zha, Yuanyuan | Malnassy, Gregory | Fulton, Noreen | Park, Jae-Hyun | Stock, Wendy | Nakamura, Yusuke | Gajewski, Thomas F. | Liu, Hongtao | Ju, Xiaoming | Kosoff, Rachelle | Ramos, Kimberly | Coder, Brandon | Petit, Robert | Princiotta, Michael | Perry, Kyle | Zou, Jun | Arina, Ainhoa | Fernandez, Christian | Zheng, Wenxin | Beckett, Michael A. | Mauceri, Helena J. | Fu, Yang-Xin | Weichselbaum, Ralph R. | DeBenedette, Mark | Lewis, Whitney | Gamble, Alicia | Nicolette, Charles | Han, Yanyan | Wu, Yeting | Yang, Chou | Huang, Jing | Wu, Dongyun | Li, Jin | Liang, Xiaoling | Zhou, Xiangjun | Hou, Jinlin | Hassan, Raffit | Jahan, Thierry | Antonia, Scott J. | Kindler, Hedy L. | Alley, Evan W. | Honarmand, Somayeh | Liu, Weiqun | Leong, Meredith L. | Whiting, Chan C. | Nair, Nitya | Enstrom, Amanda | Lemmens, Edward E. | Tsujikawa, Takahiro | Kumar, Sushil | Coussens, Lisa M. | Murphy, Aimee L. | Brockstedt, Dirk G. | Koch, Sven D. | Sebastian, Martin | Weiss, Christian | Früh, Martin | Pless, Miklos | Cathomas, Richard | Hilbe, Wolfgang | Pall, Georg | Wehler, Thomas | Alt, Jürgen | Bischoff, Helge | Geissler, Michael | Griesinger, Frank | Kollmeier, Jens | Papachristofilou, Alexandros | Doener, Fatma | Fotin-Mleczek, Mariola | Hipp, Madeleine | Hong, Henoch S. | Kallen, Karl-Josef | Klinkhardt, Ute | Stosnach, Claudia | Scheel, Birgit | Schroeder, Andreas | Seibel, Tobias | Gnad-Vogt, Ulrike | Zippelius, Alfred | Park, Ha-Ram | Ahn, Yong-Oon | Kim, Tae Min | Kim, Soyeon | Kim, Seulki | Lee, Yu Soo | Keam, Bhumsuk | Kim, Dong-Wan | Heo, Dae Seog | Pilon-Thomas, Shari | Weber, Amy | Morse, Jennifer | Kodumudi, Krithika | Liu, Hao | Mullinax, John | Sarnaik, Amod A. | Pike, Luke | Bang, Andrew | Ott, Patrick A. | Balboni, Tracy | Taylor, Allison | Spektor, Alexander | Wilhite, Tyler | Krishnan, Monica | Cagney, Daniel | Alexander, Brian | Aizer, Ayal | Buchbinder, Elizabeth | Awad, Mark | Ghandi, Leena | Hodi, F. Stephen | Schoenfeld, Jonathan | Schwartz, Anthony L. | Nath, Pulak R. | Lessey-Morillon, Elizabeth | Ridnour, Lisa | Roberts, David D. | Segal, Neil H. | Sharma, Manish | Le, Dung T. | Ott, Patrick A. | Ferris, Robert L. | Zelenetz, Andrew D. | Neelapu, Sattva S. | Levy, Ronald | Lossos, Izidore S. | Jacobson, Caron | Ramchandren, Radhakrishnan | Godwin, John | Colevas, A. Dimitrios | Meier, Roland | Krishnan, Suba | Gu, Xuemin | Neely, Jaclyn | Suryawanshi, Satyendra | Timmerman, John | Vanpouille-Box, Claire I. | Formenti, Silvia C. | Demaria, Sandra | Wennerberg, Erik | Mediero, Aranzazu | Cronstein, Bruce N. | Formenti, Silvia C. | Demaria, Sandra | Gustafson, Michael P. | DiCostanzo, AriCeli | Wheatley, Courtney | Kim, Chul-Ho | Bornschlegl, Svetlana | Gastineau, Dennis A. | Johnson, Bruce D. | Dietz, Allan B. | MacDonald, Cameron | Bucsek, Mark | Qiao, Guanxi | Hylander, Bonnie | Repasky, Elizabeth | Turbitt, William J. | Xu, Yitong | Mastro, Andrea | Rogers, Connie J. | Withers, Sita | Wang, Ziming | Khuat, Lam T. | Dunai, Cordelia | Blazar, Bruce R. | Longo, Dan | Rebhun, Robert | Grossenbacher, Steven K. | Monjazeb, Arta | Murphy, William J. | Rowlinson, Scott | Agnello, Giulia | Alters, Susan | Lowe, David | Scharping, Nicole | Menk, Ashley V. | Whetstone, Ryan | Zeng, Xue | Delgoffe, Greg M. | Santos, Patricia M. | Menk, Ashley V. | Shi, Jian | Delgoffe, Greg M. | Butterfield, Lisa H. | Whetstone, Ryan | Menk, Ashley V. | Scharping, Nicole | Delgoffe, Greg | Nagasaka, Misako | Sukari, Ammar | Byrne-Steele, Miranda | Pan, Wenjing | Hou, Xiaohong | Brown, Brittany | Eisenhower, Mary | Han, Jian | Collins, Natalie | Manguso, Robert | Pope, Hans | Shrestha, Yashaswi | Boehm, Jesse | Haining, W. Nicholas | Cron, Kyle R. | Sivan, Ayelet | Aquino-Michaels, Keston | Gajewski, Thomas F. | Orecchioni, Marco | Bedognetti, Davide | Hendrickx, Wouter | Fuoco, Claudia | Spada, Filomena | Sgarrella, Francesco | Cesareni, Gianni | Marincola, Francesco | Kostarelos, Kostas | Bianco, Alberto | Delogu, Lucia | Hendrickx, Wouter | Roelands, Jessica | Boughorbel, Sabri | Decock, Julie | Presnell, Scott | Wang, Ena | Marincola, Franco M. | Kuppen, Peter | Ceccarelli, Michele | Rinchai, Darawan | Chaussabel, Damien | Miller, Lance | Bedognetti, Davide | Nguyen, Andrew | Sanborn, J. Zachary | Vaske, Charles | Rabizadeh, Shahrooz | Niazi, Kayvan | Benz, Steven | Patel, Shashank | Restifo, Nicholas | White, James | Angiuoli, Sam | Sausen, Mark | Jones, Sian | Sevdali, Maria | Simmons, John | Velculescu, Victor | Diaz, Luis | Zhang, Theresa | Sims, Jennifer S. | Barton, Sunjay M. | Gartrell, Robyn | Kadenhe-Chiweshe, Angela | Dela Cruz, Filemon | Turk, Andrew T. | Lu, Yan | Mazzeo, Christopher F. | Kung, Andrew L. | Bruce, Jeffrey N. | Saenger, Yvonne M. | Yamashiro, Darrell J. | Connolly, Eileen P. | Baird, Jason | Crittenden, Marka | Friedman, David | Xiao, Hong | Leidner, Rom | Bell, Bryan | Young, Kristina | Gough, Michael | Bian, Zhen | Kidder, Koby | Liu, Yuan | Curran, Emily | Chen, Xiufen | Corrales, Leticia P. | Kline, Justin | Dunai, Cordelia | Aguilar, Ethan G. | Khuat, Lam T. | Murphy, William J. | Guerriero, Jennifer | Sotayo, Alaba | Ponichtera, Holly | Pourzia, Alexandra | Schad, Sara | Carrasco, Ruben | Lazo, Suzan | Bronson, Roderick | Letai, Anthony | Kornbluth, Richard S. | Gupta, Sachin | Termini, James | Guirado, Elizabeth | Stone, Geoffrey W. | Meyer, Christina | Helming, Laura | Tumang, Joseph | Wilson, Nicholas | Hofmeister, Robert | Radvanyi, Laszlo | Neubert, Natalie J. | Tillé, Laure | Barras, David | Soneson, Charlotte | Baumgaertner, Petra | Rimoldi, Donata | Gfeller, David | Delorenzi, Mauro | Fuertes Marraco, Silvia A. | Speiser, Daniel E. | Abraham, Tara S. | Xiang, Bo | Magee, Michael S. | Waldman, Scott A. | Snook, Adam E. | Blogowski, Wojciech | Zuba-Surma, Ewa | Budkowska, Marta | Salata, Daria | Dolegowska, Barbara | Starzynska, Teresa | Chan, Leo | Somanchi, Srinivas | McCulley, Kelsey | Lee, Dean | Buettner, Nico | Shi, Feng | Myers, Paisley T. | Curbishley, Stuart | Penny, Sarah A. | Steadman, Lora | Millar, David | Speers, Ellen | Ruth, Nicola | Wong, Gabriel | Thimme, Robert | Adams, David | Cobbold, Mark | Thomas, Remy | Hendrickx, Wouter | Al-Muftah, Mariam | Decock, Julie | Wong, Michael KK | Morse, Michael | McDermott, David F. | Clark, Joseph I. | Kaufman, Howard L. | Daniels, Gregory A. | Hua, Hong | Rao, Tharak | Dutcher, Janice P. | Kang, Kai | Saunthararajah, Yogen | Velcheti, Vamsidhar | Kumar, Vikas | Anwar, Firoz | Verma, Amita | Chheda, Zinal | Kohanbash, Gary | Sidney, John | Okada, Kaori | Shrivastav, Shruti | Carrera, Diego A. | Liu, Shuming | Jahan, Naznin | Mueller, Sabine | Pollack, Ian F. | Carcaboso, Angel M. | Sette, Alessandro | Hou, Yafei | Okada, Hideho | Field, Jessica J. | Zeng, Weiping | Shih, Vincent FS | Law, Che-Leung | Senter, Peter D. | Gardai, Shyra J. | Okeley, Nicole M. | Penny, Sarah A. | Abelin, Jennifer G. | Saeed, Abu Z. | Malaker, Stacy A. | Myers, Paisley T. | Shabanowitz, Jeffrey | Ward, Stephen T. | Hunt, Donald F. | Cobbold, Mark | Profusek, Pam | Wood, Laura | Shepard, Dale | Grivas, Petros | Kapp, Kerstin | Volz, Barbara | Oswald, Detlef | Wittig, Burghardt | Schmidt, Manuel | Sefrin, Julian P. | Hillringhaus, Lars | Lifke, Valeria | Lifke, Alexander | Skaletskaya, Anna | Ponte, Jose | Chittenden, Thomas | Setiady, Yulius | Valsesia-Wittmann, Sandrine | Sivado, Eva | Thomas, Vincent | El Alaoui, Meddy | Papot, Sébastien | Dumontet, Charles | Dyson, Mike | McCafferty, John | El Alaoui, Said | Verma, Amita | Kumar, Vikas | Bommareddy, Praveen K. | Kaufman, Howard L. | Zloza, Andrew | Kohlhapp, Frederick | Silk, Ann W. | Jhawar, Sachin | Paneque, Tomas | Bommareddy, Praveen K. | Kohlhapp, Frederick | Newman, Jenna | Beltran, Pedro | Zloza, Andrew | Kaufman, Howard L. | Cao, Felicia | Hong, Bang-Xing | Rodriguez-Cruz, Tania | Song, Xiao-Tong | Gottschalk, Stephen | Calderon, Hugo | Illingworth, Sam | Brown, Alice | Fisher, Kerry | Seymour, Len | Champion, Brian | Eriksson, Emma | Wenthe, Jessica | Hellström, Ann-Charlotte | Paul-Wetterberg, Gabriella | Loskog, Angelica | Eriksson, Emma | Milenova, Ioanna | Wenthe, Jessica | Ståhle, Magnus | Jarblad-Leja, Justyna | Ullenhag, Gustav | Dimberg, Anna | Moreno, Rafael | Alemany, Ramon | Loskog, Angelica | Eriksson, Emma | Milenova, Ioanna | Moreno, Rafael | Alemany, Ramon
Journal for Immunotherapy of Cancer  2016;4(Suppl 1):107-221.
doi:10.1186/s40425-016-0173-6
PMCID: PMC5123381
15.  No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer 
Hollestelle, Antoinette | van der Baan, Frederieke H. | Berchuck, Andrew | Johnatty, Sharon E. | Aben, Katja K. | Agnarsson, Bjarni A. | Aittomäki, Kristiina | Alducci, Elisa | Andrulis, Irene L. | Anton-Culver, Hoda | Antonenkova, Natalia N. | Antoniou, Antonis C. | Apicella, Carmel | Arndt, Volker | Arnold, Norbert | Arun, Banu K. | Arver, Brita | Ashworth, Alan | Baglietto, Laura | Balleine, Rosemary | Bandera, Elisa V. | Barrowdale, Daniel | Bean, Yukie T. | Beckmann, Lars | Beckmann, Matthias W. | Benitez, Javier | Berger, Andreas | Berger, Raanan | Beuselinck, Benoit | Bisogna, Maria | Bjorge, Line | Blomqvist, Carl | Bogdanova, Natalia V. | Bojesen, Anders | Bojesen, Stig E. | Bolla, Manjeet K. | Bonanni, Bernardo | Brand, Judith S. | Brauch, Hiltrud | Brenner, Hermann | Brinton, Louise | Brooks-Wilson, Angela | Bruinsma, Fiona | Brunet, Joan | Brüning, Thomas | Budzilowska, Agnieszka | Bunker, Clareann H. | Burwinkel, Barbara | Butzow, Ralf | Buys, Saundra S. | Caligo, Maria A. | Campbell, Ian | Carter, Jonathan | Chang-Claude, Jenny | Chanock, Stephen J. | Claes, Kathleen B.M. | Collée, J. Margriet | Cook, Linda S. | Couch, Fergus J. | Cox, Angela | Cramer, Daniel | Cross, Simon S. | Cunningham, Julie M. | Cybulski, Cezary | Czene, Kamila | Damiola, Francesca | Dansonka-Mieszkowska, Agnieszka | Darabi, Hatef | de la Hoya, Miguel | deFazio, Anna | Dennis, Joseph | Devilee, Peter | Dicks, Ed M. | Diez, Orland | Doherty, Jennifer A. | Domchek, Susan M. | Dorfling, Cecilia M. | Dörk, Thilo | Santos Silva, Isabel Dos | du Bois, Andreas | Dumont, Martine | Dunning, Alison M. | Duran, Mercedes | Easton, Douglas F. | Eccles, Diana | Edwards, Robert P. | Ehrencrona, Hans | Ejlertsen, Bent | Ekici, Arif B. | Ellis, Steve D. | Engel, Christoph | Eriksson, Mikael | Fasching, Peter A. | Feliubadalo, Lidia | Figueroa, Jonine | Flesch-Janys, Dieter | Fletcher, Olivia | Fontaine, Annette | Fortuzzi, Stefano | Fostira, Florentia | Fridley, Brooke L. | Friebel, Tara | Friedman, Eitan | Friel, Grace | Frost, Debra | Garber, Judy | García-Closas, Montserrat | Gayther, Simon A. | Gentry-Maharaj, Aleksandra | Gerdes, Anne-Marie | Giles, Graham G. | Glasspool, Rosalind | Glendon, Gord | Godwin, Andrew K. | Goodman, Marc T. | Gore, Martin | Greene, Mark H. | Grip, Mervi | Gronwald, Jacek | Kaulich, Daphne Gschwantler | Guénel, Pascal | Guzman, Starr R. | Haeberle, Lothar | Haiman, Christopher A. | Hall, Per | Halverson, Sandra L. | Hamann, Ute | Hansen, Thomas V.O. | Harter, Philipp | Hartikainen, Jaana M. | Healey, Sue | Hein, Alexander | Heitz, Florian | Henderson, Brian E. | Herzog, Josef | Hildebrandt, Michelle A. T. | Høgdall, Claus K. | Høgdall, Estrid | Hogervorst, Frans B.L. | Hopper, John L. | Humphreys, Keith | Huzarski, Tomasz | Imyanitov, Evgeny N. | Isaacs, Claudine | Jakubowska, Anna | Janavicius, Ramunas | Jaworska, Katarzyna | Jensen, Allan | Jensen, Uffe Birk | Johnson, Nichola | Jukkola-Vuorinen, Arja | Kabisch, Maria | Karlan, Beth Y. | Kataja, Vesa | Kauff, Noah | Kelemen, Linda E. | Kerin, Michael J. | Kiemeney, Lambertus A. | Kjaer, Susanne K. | Knight, Julia A. | Knol-Bout, Jacoba P. | Konstantopoulou, Irene | Kosma, Veli-Matti | Krakstad, Camilla | Kristensen, Vessela | Kuchenbaecker, Karoline B. | Kupryjanczyk, Jolanta | Laitman, Yael | Lambrechts, Diether | Lambrechts, Sandrina | Larson, Melissa C. | Lasa, Aadriana | Laurent-Puig, Pierre | Lazaro, Conxi | Le, Nhu D. | Le Marchand, Loic | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Li, Jingmei | Liang, Dong | Lindblom, Annika | Lindor, Noralane | Lissowska, Jolanta | Long, Jirong | Lu, Karen H. | Lubinski, Jan | Lundvall, Lene | Lurie, Galina | Mai, Phuong L. | Mannermaa, Arto | Margolin, Sara | Mariette, Frederique | Marme, Frederik | Martens, John W.M. | Massuger, Leon F.A.G. | Maugard, Christine | Mazoyer, Sylvie | McGuffog, Lesley | McGuire, Valerie | McLean, Catriona | McNeish, Iain | Meindl, Alfons | Menegaux, Florence | Menéndez, Primitiva | Menkiszak, Janusz | Menon, Usha | Mensenkamp, Arjen R. | Miller, Nicola | Milne, Roger L. | Modugno, Francesmary | Montagna, Marco | Moysich, Kirsten B. | Müller, Heiko | Mulligan, Anna Marie | Muranen, Taru A. | Narod, Steven A. | Nathanson, Katherine L. | Ness, Roberta B. | Neuhausen, Susan L. | Nevanlinna, Heli | Neven, Patrick | Nielsen, Finn C. | Nielsen, Sune F. | Nordestgaard, Børge G. | Nussbaum, Robert L. | Odunsi, Kunle | Offit, Kenneth | Olah, Edith | Olopade, Olufunmilayo I. | Olson, Janet E. | Olson, Sara H. | Oosterwijk, Jan C. | Orlow, Irene | Orr, Nick | Orsulic, Sandra | Osorio, Ana | Ottini, Laura | Paul, James | Pearce, Celeste L. | Pedersen, Inge Sokilde | Peissel, Bernard | Pejovic, Tanja | Pelttari, Liisa M. | Perkins, Jo | Permuth-Wey, Jenny | Peterlongo, Paolo | Peto, Julian | Phelan, Catherine M. | Phillips, Kelly-Anne | Piedmonte, Marion | Pike, Malcolm C. | Platte, Radka | Plisiecka-Halasa, Joanna | Poole, Elizabeth M. | Poppe, Bruce | Pylkäs, Katri | Radice, Paolo | Ramus, Susan J. | Rebbeck, Timothy R. | Reed, Malcolm W.R. | Rennert, Gad | Risch, Harvey A. | Robson, Mark | Rodriguez, Gustavo C. | Romero, Atocha | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo | Salani, Ritu | Salvesen, Helga B. | Sawyer, Elinor J. | Schildkraut, Joellen M. | Schmidt, Marjanka K. | Schmutzler, Rita K. | Schneeweiss, Andreas | Schoemaker, Minouk J. | Schrauder, Michael G. | Schumacher, Fredrick | Schwaab, Ira | Scuvera, Giulietta | Sellers, Thomas A. | Severi, Gianluca | Seynaeve, Caroline M. | Shah, Mitul | Shrubsole, Martha | Siddiqui, Nadeem | Sieh, Weiva | Simard, Jacques | Singer, Christian F. | Sinilnikova, Olga M. | Smeets, Dominiek | Sohn, Christof | Soller, Maria | Song, Honglin | Soucy, Penny | Southey, Melissa C. | Stegmaier, Christa | Stoppa-Lyonnet, Dominique | Sucheston, Lara | Swerdlow, Anthony | Tangen, Ingvild L. | Tea, Muy-Kheng | Teixeira, Manuel R. | Terry, Kathryn L. | Terry, Mary Beth | Thomassen, Madas | Thompson, Pamela J. | Tihomirova, Laima | Tischkowitz, Marc | Toland, Amanda Ewart | Tollenaar, Rob A.E.M. | Tomlinson, Ian | Torres, Diana | Truong, Thérèse | Tsimiklis, Helen | Tung, Nadine | Tworoger, Shelley S. | Tyrer, Jonathan P. | Vachon, Celine M. | Van 't Veer, Laura J. | van Altena, Anne M. | Van Asperen, C.J. | van den Berg, David | van den Ouweland, Ans M.W. | van Doorn, Helena C. | Van Nieuwenhuysen, Els | van Rensburg, Elizabeth J. | Vergote, Ignace | Verhoef, Senno | Vierkant, Robert A. | Vijai, Joseph | Vitonis, Allison F. | von Wachenfeldt, Anna | Walsh, Christine | Wang, Qin | Wang-Gohrke, Shan | Wappenschmidt, Barbara | Weischer, Maren | Weitzel, Jeffrey N. | Weltens, Caroline | Wentzensen, Nicolas | Whittemore, Alice S. | Wilkens, Lynne R. | Winqvist, Robert | Wu, Anna H. | Wu, Xifeng | Yang, Hannah P. | Zaffaroni, Daniela | Zamora, M. Pilar | Zheng, Wei | Ziogas, Argyrios | Chenevix-Trench, Georgia | Pharoah, Paul D.P. | Rookus, Matti A. | Hooning, Maartje J. | Goode, Ellen L.
Gynecologic oncology  2015;141(2):386-401.
Objective
Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370.
Methods
Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers).
Results
We found no association with risk of ovarian cancer (OR= 0.99, 95% CI 0.94–1.04,p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94–1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97–1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97–1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71–1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94–1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83–1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87–1.06, p = 0.38), and all other previously-reported associations.
Conclusions
rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
doi:10.1016/j.ygyno.2015.04.034
PMCID: PMC4630206  PMID: 25940428
KRAS variant; Breast cancer; Ovarian cancer; Genetic association; Clinical outcome
16.  Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus 
Lawrenson, Kate | Kar, Siddhartha | McCue, Karen | Kuchenbaeker, Karoline | Michailidou, Kyriaki | Tyrer, Jonathan | Beesley, Jonathan | Ramus, Susan J. | Li, Qiyuan | Delgado, Melissa K. | Lee, Janet M. | Aittomäki, Kristiina | Andrulis, Irene L. | Anton-Culver, Hoda | Arndt, Volker | Arun, Banu K. | Arver, Brita | Bandera, Elisa V. | Barile, Monica | Barkardottir, Rosa B. | Barrowdale, Daniel | Beckmann, Matthias W. | Benitez, Javier | Berchuck, Andrew | Bisogna, Maria | Bjorge, Line | Blomqvist, Carl | Blot, William | Bogdanova, Natalia | Bojesen, Anders | Bojesen, Stig E. | Bolla, Manjeet K. | Bonanni, Bernardo | Børresen-Dale, Anne-Lise | Brauch, Hiltrud | Brennan, Paul | Brenner, Hermann | Bruinsma, Fiona | Brunet, Joan | Buhari, Shaik Ahmad | Burwinkel, Barbara | Butzow, Ralf | Buys, Saundra S. | Cai, Qiuyin | Caldes, Trinidad | Campbell, Ian | Canniotto, Rikki | Chang-Claude, Jenny | Chiquette, Jocelyne | Choi, Ji-Yeob | Claes, Kathleen B. M. | Cook, Linda S. | Cox, Angela | Cramer, Daniel W. | Cross, Simon S. | Cybulski, Cezary | Czene, Kamila | Daly, Mary B. | Damiola, Francesca | Dansonka-Mieszkowska, Agnieszka | Darabi, Hatef | Dennis, Joe | Devilee, Peter | Diez, Orland | Doherty, Jennifer A. | Domchek, Susan M. | Dorfling, Cecilia M. | Dörk, Thilo | Dumont, Martine | Ehrencrona, Hans | Ejlertsen, Bent | Ellis, Steve | Engel, Christoph | Lee, Eunjung | Evans, D. Gareth | Fasching, Peter A. | Feliubadalo, Lidia | Figueroa, Jonine | Flesch-Janys, Dieter | Fletcher, Olivia | Flyger, Henrik | Foretova, Lenka | Fostira, Florentia | Foulkes, William D. | Fridley, Brooke L. | Friedman, Eitan | Frost, Debra | Gambino, Gaetana | Ganz, Patricia A. | Garber, Judy | García-Closas, Montserrat | Gentry-Maharaj, Aleksandra | Ghoussaini, Maya | Giles, Graham G. | Glasspool, Rosalind | Godwin, Andrew K. | Goldberg, Mark S. | Goldgar, David E. | González-Neira, Anna | Goode, Ellen L. | Goodman, Marc T. | Greene, Mark H. | Gronwald, Jacek | Guénel, Pascal | Haiman, Christopher A. | Hall, Per | Hallberg, Emily | Hamann, Ute | Hansen, Thomas V. O. | Harrington, Patricia A. | Hartman, Mikael | Hassan, Norhashimah | Healey, Sue | Heitz, Florian | Herzog, Josef | Høgdall, Estrid | Høgdall, Claus K. | Hogervorst, Frans B. L. | Hollestelle, Antoinette | Hopper, John L. | Hulick, Peter J. | Huzarski, Tomasz | Imyanitov, Evgeny N. | Isaacs, Claudine | Ito, Hidemi | Jakubowska, Anna | Janavicius, Ramunas | Jensen, Allan | John, Esther M. | Johnson, Nichola | Kabisch, Maria | Kang, Daehee | Kapuscinski, Miroslav | Karlan, Beth Y. | Khan, Sofia | Kiemeney, Lambertus A. | Kjaer, Susanne Kruger | Knight, Julia A. | Konstantopoulou, Irene | Kosma, Veli-Matti | Kristensen, Vessela | Kupryjanczyk, Jolanta | Kwong, Ava | de la Hoya, Miguel | Laitman, Yael | Lambrechts, Diether | Le, Nhu | De Leeneer, Kim | Lester, Jenny | Levine, Douglas A. | Li, Jingmei | Lindblom, Annika | Long, Jirong | Lophatananon, Artitaya | Loud, Jennifer T. | Lu, Karen | Lubinski, Jan | Mannermaa, Arto | Manoukian, Siranoush | Le Marchand, Loic | Margolin, Sara | Marme, Frederik | Massuger, Leon F. A. G. | Matsuo, Keitaro | Mazoyer, Sylvie | McGuffog, Lesley | McLean, Catriona | McNeish, Iain | Meindl, Alfons | Menon, Usha | Mensenkamp, Arjen R. | Milne, Roger L. | Montagna, Marco | Moysich, Kirsten B. | Muir, Kenneth | Mulligan, Anna Marie | Nathanson, Katherine L. | Ness, Roberta B. | Neuhausen, Susan L. | Nevanlinna, Heli | Nord, Silje | Nussbaum, Robert L. | Odunsi, Kunle | Offit, Kenneth | Olah, Edith | Olopade, Olufunmilayo I. | Olson, Janet E. | Olswold, Curtis | O'Malley, David | Orlow, Irene | Orr, Nick | Osorio, Ana | Park, Sue Kyung | Pearce, Celeste L. | Pejovic, Tanja | Peterlongo, Paolo | Pfeiler, Georg | Phelan, Catherine M. | Poole, Elizabeth M. | Pylkäs, Katri | Radice, Paolo | Rantala, Johanna | Rashid, Muhammad Usman | Rennert, Gad | Rhenius, Valerie | Rhiem, Kerstin | Risch, Harvey A. | Rodriguez, Gus | Rossing, Mary Anne | Rudolph, Anja | Salvesen, Helga B. | Sangrajrang, Suleeporn | Sawyer, Elinor J. | Schildkraut, Joellen M. | Schmidt, Marjanka K. | Schmutzler, Rita K. | Sellers, Thomas A. | Seynaeve, Caroline | Shah, Mitul | Shen, Chen-Yang | Shu, Xiao-Ou | Sieh, Weiva | Singer, Christian F. | Sinilnikova, Olga M. | Slager, Susan | Song, Honglin | Soucy, Penny | Southey, Melissa C. | Stenmark-Askmalm, Marie | Stoppa-Lyonnet, Dominique | Sutter, Christian | Swerdlow, Anthony | Tchatchou, Sandrine | Teixeira, Manuel R. | Teo, Soo H. | Terry, Kathryn L. | Terry, Mary Beth | Thomassen, Mads | Tibiletti, Maria Grazia | Tihomirova, Laima | Tognazzo, Silvia | Toland, Amanda Ewart | Tomlinson, Ian | Torres, Diana | Truong, Thérèse | Tseng, Chiu-chen | Tung, Nadine | Tworoger, Shelley S. | Vachon, Celine | van den Ouweland, Ans M. W. | van Doorn, Helena C. | van Rensburg, Elizabeth J. | Van't Veer, Laura J. | Vanderstichele, Adriaan | Vergote, Ignace | Vijai, Joseph | Wang, Qin | Wang-Gohrke, Shan | Weitzel, Jeffrey N. | Wentzensen, Nicolas | Whittemore, Alice S. | Wildiers, Hans | Winqvist, Robert | Wu, Anna H. | Yannoukakos, Drakoulis | Yoon, Sook-Yee | Yu, Jyh-Cherng | Zheng, Wei | Zheng, Ying | Khanna, Kum Kum | Simard, Jacques | Monteiro, Alvaro N. | French, Juliet D. | Couch, Fergus J. | Freedman, Matthew L. | Easton, Douglas F. | Dunning, Alison M. | Pharoah, Paul D. | Edwards, Stacey L. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Gayther, Simon A.
Nature Communications  2016;7:12675.
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10−20), ER-negative BC (P=1.1 × 10−13), BRCA1-associated BC (P=7.7 × 10−16) and triple negative BC (P-diff=2 × 10−5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10−3) and ABHD8 (P<2 × 10−3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.
doi:10.1038/ncomms12675
PMCID: PMC5023955  PMID: 27601076
17.  PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS 
Southey, Melissa C | Goldgar, David E | Winqvist, Robert | Pylkäs, Katri | Couch, Fergus | Tischkowitz, Marc | Foulkes, William D | Dennis, Joe | Michailidou, Kyriaki | van Rensburg, Elizabeth J | Heikkinen, Tuomas | Nevanlinna, Heli | Hopper, John L | Dörk, Thilo | Claes, Kathleen BM | Reis-Filho, Jorge | Teo, Zhi Ling | Radice, Paolo | Catucci, Irene | Peterlongo, Paolo | Tsimiklis, Helen | Odefrey, Fabrice A | Dowty, James G | Schmidt, Marjanka K | Broeks, Annegien | Hogervorst, Frans B | Verhoef, Senno | Carpenter, Jane | Clarke, Christine | Scott, Rodney J | Fasching, Peter A | Haeberle, Lothar | Ekici, Arif B | Beckmann, Matthias W | Peto, Julian | dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Bolla, Manjeet K | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Marme, Federik | Burwinkel, Barbara | Yang, Rongxi | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Sanchez, Marie | Bojesen, Stig | Nielsen, Sune F | Flyger, Henrik | Benitez, Javier | Zamora, M Pilar | Perez, Jose Ignacio Arias | Menéndez, Primitiva | Anton-Culver, Hoda | Neuhausen, Susan | Ziogas, Argyrios | Clarke, Christina A | Brenner, Hermann | Arndt, Volker | Stegmaier, Christa | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Bogdanova, Natalia V | Antonenkova, Natalia N | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Spurdle, Amanda B | Investigators, kConFab | Wauters, Els | Smeets, Dominiek | Beuselinck, Benoit | Floris, Giuseppe | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Olson, Janet E | Vachon, Celine | Pankratz, Vernon S | McLean, Catriona | Haiman, Christopher A | Henderson, Brian E | Schumacher, Fredrick | Le Marchand, Loic | Kristensen, Vessela | Alnæs, Grethe Grenaker | Zheng, Wei | Hunter, David J | Lindstrom, Sara | Hankinson, Susan E | Kraft, Peter | Andrulis, Irene | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Jukkola-Vuorinen, Arja | Grip, Mervi | Kauppila, Saila | Devilee, Peter | Tollenaar, Robert A E M | Seynaeve, Caroline | Hollestelle, Antoinette | Garcia-Closas, Montserrat | Figueroa, Jonine | Chanock, Stephen J | Lissowska, Jolanta | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Eccles, Diana M | Rafiq, Sajjad | Tapper, William J | Gerty, Sue M | Hooning, Maartje J | Martens, John W M | Collée, J Margriet | Tilanus-Linthorst, Madeleine | Hall, Per | Li, Jingmei | Brand, Judith S | Humphreys, Keith | Cox, Angela | Reed, Malcolm W R | Luccarini, Craig | Baynes, Caroline | Dunning, Alison M | Hamann, Ute | Torres, Diana | Ulmer, Hans Ulrich | Rüdiger, Thomas | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Slager, Susan | Toland, Amanda E | Ambrosone, Christine B | Yannoukakos, Drakoulis | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | González-Neira, Anna | Pita, Guillermo | Alonso, M Rosario | Álvarez, Nuria | Herrero, Daniel | Tessier, Daniel C | Vincent, Daniel | Bacot, Francois | Simard, Jacques | Dumont, Martine | Soucy, Penny | Eeles, Rosalind | Muir, Kenneth | Wiklund, Fredrik | Gronberg, Henrik | Schleutker, Johanna | Nordestgaard, Børge G | Weischer, Maren | Travis, Ruth C | Neal, David | Donovan, Jenny L | Hamdy, Freddie C | Khaw, Kay-Tee | Stanford, Janet L | Blot, William J | Thibodeau, Stephen | Schaid, Daniel J | Kelley, Joseph L | Maier, Christiane | Kibel, Adam S | Cybulski, Cezary | Cannon-Albright, Lisa | Butterbach, Katja | Park, Jong | Kaneva, Radka | Batra, Jyotsna | Teixeira, Manuel R | Kote-Jarai, Zsofia | Olama, Ali Amin Al | Benlloch, Sara | Renner, Stefan P | Hartmann, Arndt | Hein, Alexander | Ruebner, Matthias | Lambrechts, Diether | Van Nieuwenhuysen, Els | Vergote, Ignace | Lambretchs, Sandrina | Doherty, Jennifer A | Rossing, Mary Anne | Nickels, Stefan | Eilber, Ursula | Wang-Gohrke, Shan | Odunsi, Kunle | Sucheston-Campbell, Lara E | Friel, Grace | Lurie, Galina | Killeen, Jeffrey L | Wilkens, Lynne R | Goodman, Marc T | Runnebaum, Ingo | Hillemanns, Peter A | Pelttari, Liisa M | Butzow, Ralf | Modugno, Francesmary | Edwards, Robert P | Ness, Roberta B | Moysich, Kirsten B | du Bois, Andreas | Heitz, Florian | Harter, Philipp | Kommoss, Stefan | Karlan, Beth Y | Walsh, Christine | Lester, Jenny | Jensen, Allan | Kjaer, Susanne Krüger | Høgdall, Estrid | Peissel, Bernard | Bonanni, Bernardo | Bernard, Loris | Goode, Ellen L | Fridley, Brooke L | Vierkant, Robert A | Cunningham, Julie M | Larson, Melissa C | Fogarty, Zachary C | Kalli, Kimberly R | Liang, Dong | Lu, Karen H | Hildebrandt, Michelle A T | Wu, Xifeng | Levine, Douglas A | Dao, Fanny | Bisogna, Maria | Berchuck, Andrew | Iversen, Edwin S | Marks, Jeffrey R | Akushevich, Lucy | Cramer, Daniel W | Schildkraut, Joellen | Terry, Kathryn L | Poole, Elizabeth M | Stampfer, Meir | Tworoger, Shelley S | Bandera, Elisa V | Orlow, Irene | Olson, Sara H | Bjorge, Line | Salvesen, Helga B | van Altena, Anne M | Aben, Katja K H | Kiemeney, Lambertus A | Massuger, Leon F A G | Pejovic, Tanja | Bean, Yukie | Brooks-Wilson, Angela | Kelemen, Linda E | Cook, Linda S | Le, Nhu D | Górski, Bohdan | Gronwald, Jacek | Menkiszak, Janusz | Høgdall, Claus K | Lundvall, Lene | Nedergaard, Lotte | Engelholm, Svend Aage | Dicks, Ed | Tyrer, Jonathan | Campbell, Ian | McNeish, Iain | Paul, James | Siddiqui, Nadeem | Glasspool, Rosalind | Whittemore, Alice S | Rothstein, Joseph H | McGuire, Valerie | Sieh, Weiva | Cai, Hui | Shu, Xiao-Ou | Teten, Rachel T | Sutphen, Rebecca | McLaughlin, John R | Narod, Steven A | Phelan, Catherine M | Monteiro, Alvaro N | Fenstermacher, David | Lin, Hui-Yi | Permuth, Jennifer B | Sellers, Thomas A | Chen, Y Ann | Tsai, Ya-Yu | Chen, Zhihua | Gentry-Maharaj, Aleksandra | Gayther, Simon A | Ramus, Susan J | Menon, Usha | Wu, Anna H | Pearce, Celeste L | Van Den Berg, David | Pike, Malcolm C | Dansonka-Mieszkowska, Agnieszka | Plisiecka-Halasa, Joanna | Moes-Sosnowska, Joanna | Kupryjanczyk, Jolanta | Pharoah, Paul DP | Song, Honglin | Winship, Ingrid | Chenevix-Trench, Georgia | Giles, Graham G | Tavtigian, Sean V | Easton, Doug F | Milne, Roger L
Journal of Medical Genetics  2016;53(12):800-811.
Background
The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.
Methods
We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.
Results
For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.
Conclusions
This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
doi:10.1136/jmedgenet-2016-103839
PMCID: PMC5200636  PMID: 27595995
Cancer: breast; Cancer: prostate; Genetics; Cancer: ovary; cancer predisposition
18.  PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS 
Southey, Melissa C | Goldgar, David E | Winqvist, Robert | Pylkäs, Katri | Couch, Fergus | Tischkowitz, Marc | Foulkes, William D | Dennis, Joe | Michailidou, Kyriaki | van Rensburg, Elizabeth J | Heikkinen, Tuomas | Nevanlinna, Heli | Hopper, John L | Dörk, Thilo | Claes, Kathleen BM | Reis-Filho, Jorge | Teo, Zhi Ling | Radice, Paolo | Catucci, Irene | Peterlongo, Paolo | Tsimiklis, Helen | Odefrey, Fabrice A | Dowty, James G | Schmidt, Marjanka K | Broeks, Annegien | Hogervorst, Frans B | Verhoef, Senno | Carpenter, Jane | Clarke, Christine | Scott, Rodney J | Fasching, Peter A | Haeberle, Lothar | Ekici, Arif B | Beckmann, Matthias W | Peto, Julian | dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Bolla, Manjeet K | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Marme, Federik | Burwinkel, Barbara | Yang, Rongxi | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Sanchez, Marie | Bojesen, Stig | Nielsen, Sune F | Flyger, Henrik | Benitez, Javier | Zamora, M Pilar | Arias Perez, Jose Ignacio | Menéndez, Primitiva | Anton-Culver, Hoda | Neuhausen, Susan | Ziogas, Argyrios | Clarke, Christina A | Brenner, Hermann | Arndt, Volker | Stegmaier, Christa | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Bogdanova, Natalia V | Antonenkova, Natalia N | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Spurdle, Amanda B | Wauters, Els | Smeets, Dominiek | Beuselinck, Benoit | Floris, Giuseppe | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Olson, Janet E | Vachon, Celine | Pankratz, Vernon S | McLean, Catriona | Haiman, Christopher A | Henderson, Brian E | Schumacher, Fredrick | Le Marchand, Loic | Kristensen, Vessela | Alnæs, Grethe Grenaker | Zheng, Wei | Hunter, David J | Lindstrom, Sara | Hankinson, Susan E | Kraft, Peter | Andrulis, Irene | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Jukkola-Vuorinen, Arja | Grip, Mervi | Kauppila, Saila | Devilee, Peter | Tollenaar, Robert A E M | Seynaeve, Caroline | Hollestelle, Antoinette | Garcia-Closas, Montserrat | Figueroa, Jonine | Chanock, Stephen J | Lissowska, Jolanta | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Eccles, Diana M | Rafiq, Sajjad | Tapper, William J | Gerty, Sue M | Hooning, Maartje J | Martens, John W M | Collée, J Margriet | Tilanus-Linthorst, Madeleine | Hall, Per | Li, Jingmei | Brand, Judith S | Humphreys, Keith | Cox, Angela | Reed, Malcolm W R | Luccarini, Craig | Baynes, Caroline | Dunning, Alison M | Hamann, Ute | Torres, Diana | Ulmer, Hans Ulrich | Rüdiger, Thomas | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Slager, Susan | Toland, Amanda E | Ambrosone, Christine B | Yannoukakos, Drakoulis | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | González-Neira, Anna | Pita, Guillermo | Alonso, M Rosario | Álvarez, Nuria | Herrero, Daniel | Tessier, Daniel C | Vincent, Daniel | Bacot, Francois | Simard, Jacques | Dumont, Martine | Soucy, Penny | Eeles, Rosalind | Muir, Kenneth | Wiklund, Fredrik | Gronberg, Henrik | Schleutker, Johanna | Nordestgaard, Børge G | Weischer, Maren | Travis, Ruth C | Neal, David | Donovan, Jenny L | Hamdy, Freddie C | Khaw, Kay-Tee | Stanford, Janet L | Blot, William J | Thibodeau, Stephen | Schaid, Daniel J | Kelley, Joseph L | Maier, Christiane | Kibel, Adam S | Cybulski, Cezary | Cannon-Albright, Lisa | Butterbach, Katja | Park, Jong | Kaneva, Radka | Batra, Jyotsna | Teixeira, Manuel R | Kote-Jarai, Zsofia | Al Olama, Ali Amin | Benlloch, Sara | Renner, Stefan P | Hartmann, Arndt | Hein, Alexander | Ruebner, Matthias | Lambrechts, Diether | Van Nieuwenhuysen, Els | Vergote, Ignace | Lambretchs, Sandrina | Doherty, Jennifer A | Rossing, Mary Anne | Nickels, Stefan | Eilber, Ursula | Wang-Gohrke, Shan | Odunsi, Kunle | Sucheston-Campbell, Lara E | Friel, Grace | Lurie, Galina | Killeen, Jeffrey L | Wilkens, Lynne R | Goodman, Marc T | Runnebaum, Ingo | Hillemanns, Peter A | Pelttari, Liisa M | Butzow, Ralf | Modugno, Francesmary | Edwards, Robert P | Ness, Roberta B | Moysich, Kirsten B | du Bois, Andreas | Heitz, Florian | Harter, Philipp | Kommoss, Stefan | Karlan, Beth Y | Walsh, Christine | Lester, Jenny | Jensen, Allan | Kjaer, Susanne Krüger | Høgdall, Estrid | Peissel, Bernard | Bonanni, Bernardo | Bernard, Loris | Goode, Ellen L | Fridley, Brooke L | Vierkant, Robert A | Cunningham, Julie M | Larson, Melissa C | Fogarty, Zachary C | Kalli, Kimberly R | Liang, Dong | Lu, Karen H | Hildebrandt, Michelle A T | Wu, Xifeng | Levine, Douglas A | Dao, Fanny | Bisogna, Maria | Berchuck, Andrew | Iversen, Edwin S | Marks, Jeffrey R | Akushevich, Lucy | Cramer, Daniel W | Schildkraut, Joellen | Terry, Kathryn L | Poole, Elizabeth M | Stampfer, Meir | Tworoger, Shelley S | Bandera, Elisa V | Orlow, Irene | Olson, Sara H | Bjorge, Line | Salvesen, Helga B | van Altena, Anne M | Aben, Katja K H | Kiemeney, Lambertus A | Massuger, Leon F A G | Pejovic, Tanja | Bean, Yukie | Brooks-Wilson, Angela | Kelemen, Linda E | Cook, Linda S | Le, Nhu D | Górski, Bohdan | Gronwald, Jacek | Menkiszak, Janusz | Høgdall, Claus K | Lundvall, Lene | Nedergaard, Lotte | Engelholm, Svend Aage | Dicks, Ed | Tyrer, Jonathan | Campbell, Ian | McNeish, Iain | Paul, James | Siddiqui, Nadeem | Glasspool, Rosalind | Whittemore, Alice S | Rothstein, Joseph H | McGuire, Valerie | Sieh, Weiva | Cai, Hui | Shu, Xiao-Ou | Teten, Rachel T | Sutphen, Rebecca | McLaughlin, John R | Narod, Steven A | Phelan, Catherine M | Monteiro, Alvaro N | Fenstermacher, David | Lin, Hui-Yi | Permuth, Jennifer B | Sellers, Thomas A | Chen, Y Ann | Tsai, Ya-Yu | Chen, Zhihua | Gentry-Maharaj, Aleksandra | Gayther, Simon A | Ramus, Susan J | Menon, Usha | Wu, Anna H | Pearce, Celeste L | Van Den Berg, David | Pike, Malcolm C | Dansonka-Mieszkowska, Agnieszka | Plisiecka-Halasa, Joanna | Moes-Sosnowska, Joanna | Kupryjanczyk, Jolanta | Pharoah, Paul DP | Song, Honglin | Winship, Ingrid | Chenevix-Trench, Georgia | Giles, Graham G | Tavtigian, Sean V | Easton, Doug F | Milne, Roger L
Journal of medical genetics  2016;53(12):800-811.
Background
The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.
Methods
We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.
Results
For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.
Conclusions
This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
doi:10.1136/jmedgenet-2016-103839
PMCID: PMC5200636  PMID: 27595995
19.  Genome-wide Meta-analyses of Breast, Ovarian and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by At Least Two Cancer Types 
Kar, Siddhartha P. | Beesley, Jonathan | Al Olama, Ali Amin | Michailidou, Kyriaki | Tyrer, Jonathan | Kote-Jarai, ZSofia | Lawrenson, Kate | Lindstrom, Sara | Ramus, Susan J. | Thompson, Deborah J. | Kibel, Adam S. | Dansonka-Mieszkowska, Agnieszka | Michael, Agnieszka | Dieffenbach, Aida K. | Gentry-Maharaj, Aleksandra | Whittemore, Alice S. | Wolk, Alicja | Monteiro, Alvaro | Peixoto, Ana | Kierzek, Andrzej | Cox, Angela | Rudolph, Anja | Gonzalez-Neira, Anna | Wu, Anna H. | Lindblom, Annika | Swerdlow, Anthony | Ziogas, Argyrios | Ekici, Arif B. | Burwinkel, Barbara | Karlan, Beth Y. | Nordestgaard, Børge G. | Blomqvist, Carl | Phelan, Catherine | McLean, Catriona | Pearce, Celeste Leigh | Vachon, Celine | Cybulski, Cezary | Slavov, Chavdar | Stegmaier, Christa | Maier, Christiane | Ambrosone, Christine B. | Høgdall, Claus K. | Teerlink, Craig C. | Kang, Daehee | Tessier, Daniel C. | Schaid, Daniel J. | Stram, Daniel O. | Cramer, Daniel W. | Neal, David E. | Eccles, Diana | Flesch-Janys, Dieter | Velez Edwards, Digna R. | Wokozorczyk, Dominika | Levine, Douglas A. | Yannoukakos, Drakoulis | Sawyer, Elinor J. | Bandera, Elisa V. | Poole, Elizabeth M. | Goode, Ellen L. | Khusnutdinova, Elza | Høgdall, Estrid | Song, Fengju | Bruinsma, Fiona | Heitz, Florian | Modugno, Francesmary | Hamdy, Freddie C. | Wiklund, Fredrik | Giles, Graham G. | Olsson, Håkan | Wildiers, Hans | Ulmer, Hans-Ulrich | Pandha, Hardev | Risch, Harvey A. | Darabi, Hatef | Salvesen, Helga B. | Nevanlinna, Heli | Gronberg, Henrik | Brenner, Hermann | Brauch, Hiltrud | Anton-Culver, Hoda | Song, Honglin | Lim, Hui-Yi | McNeish, Iain | Campbell, Ian | Vergote, Ignace | Gronwald, Jacek | Lubiński, Jan | Stanford, Janet L. | Benítez, Javier | Doherty, Jennifer A. | Permuth, Jennifer B. | Chang-Claude, Jenny | Donovan, Jenny L. | Dennis, Joe | Schildkraut, Joellen M. | Schleutker, Johanna | Hopper, John L. | Kupryjanczyk, Jolanta | Park, Jong Y. | Figueroa, Jonine | Clements, Judith A. | Knight, Julia A. | Peto, Julian | Cunningham, Julie M. | Pow-Sang, Julio | Batra, Jyotsna | Czene, Kamila | Lu, Karen H. | Herkommer, Kathleen | Khaw, Kay-Tee | Matsuo, Keitaro | Muir, Kenneth | Offitt, Kenneth | Chen, Kexin | Moysich, Kirsten B. | Aittomäki, Kristiina | Odunsi, Kunle | Kiemeney, Lambertus A. | Massuger, Leon F.A.G. | Fitzgerald, Liesel M. | Cook, Linda S. | Cannon-Albright, Lisa | Hooning, Maartje J. | Pike, Malcolm C. | Bolla, Manjeet K. | Luedeke, Manuel | Teixeira, Manuel R. | Goodman, Marc T. | Schmidt, Marjanka K. | Riggan, Marjorie | Aly, Markus | Rossing, Mary Anne | Beckmann, Matthias W. | Moisse, Matthieu | Sanderson, Maureen | Southey, Melissa C. | Jones, Michael | Lush, Michael | Hildebrandt, Michelle A. T. | Hou, Ming-Feng | Schoemaker, Minouk J. | Garcia-Closas, Montserrat | Bogdanova, Natalia | Rahman, Nazneen | Le, Nhu D. | Orr, Nick | Wentzensen, Nicolas | Pashayan, Nora | Peterlongo, Paolo | Guénel, Pascal | Brennan, Paul | Paulo, Paula | Webb, Penelope M. | Broberg, Per | Fasching, Peter A. | Devilee, Peter | Wang, Qin | Cai, Qiuyin | Li, Qiyuan | Kaneva, Radka | Butzow, Ralf | Kopperud, Reidun Kristin | Schmutzler, Rita K. | Stephenson, Robert A. | MacInnis, Robert J. | Hoover, Robert N. | Winqvist, Robert | Ness, Roberta | Milne, Roger L. | Travis, Ruth C. | Benlloch, Sara | Olson, Sara H. | McDonnell, Shannon K. | Tworoger, Shelley S. | Maia, Sofia | Berndt, Sonja | Lee, Soo Chin | Teo, Soo-Hwang | Thibodeau, Stephen N. | Bojesen, Stig E. | Gapstur, Susan M. | Kjær, Susanne Krüger | Pejovic, Tanja | Tammela, Teuvo L.J. | Dörk, Thilo | Brüning, Thomas | Wahlfors, Tiina | Key, Tim J. | Edwards, Todd L. | Menon, Usha | Hamann, Ute | Mitev, Vanio | Kosma, Veli-Matti | Setiawan, Veronica Wendy | Kristensen, Vessela | Arndt, Volker | Vogel, Walther | Zheng, Wei | Sieh, Weiva | Blot, William J. | Kluzniak, Wojciech | Shu, Xiao-Ou | Gao, Yu-Tang | Schumacher, Fredrick | Freedman, Matthew L. | Berchuck, Andrew | Dunning, Alison M. | Simard, Jacques | Haiman, Christopher A. | Spurdle, Amanda | Sellers, Thomas A. | Hunter, David J. | Henderson, Brian E. | Kraft, Peter | Chanock, Stephen J. | Couch, Fergus J. | Hall, Per | Gayther, Simon A. | Easton, Douglas F. | Chenevix-Trench, Georgia | Eeles, Rosalind | Pharoah, Paul D.P. | Lambrechts, Diether
Cancer discovery  2016;6(9):1052-1067.
Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis.
doi:10.1158/2159-8290.CD-15-1227
PMCID: PMC5010513  PMID: 27432226
breast cancer; ovarian cancer; prostate cancer; genome-wide association studies; pleiotropy
20.  Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization 
Zhang, Ben | Shu, Xiao-Ou | Delahanty, Ryan J. | Zeng, Chenjie | Michailidou, Kyriaki | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Wen, Wanqing | Long, Jirong | Li, Chun | Dunning, Alison M. | Chang-Claude, Jenny | Shah, Mitul | Perkins, Barbara J. | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Lambrechts, Diether | Neven, Patrick | Wildiers, Hans | Floris, Giuseppe | Schmidt, Marjanka K. | Rookus, Matti A. | van den Hurk, Katja | de Kort, Wim L. A. M. | Couch, Fergus J. | Olson, Janet E. | Hallberg, Emily | Vachon, Celine | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Peto, Julian | dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Li, Jingmei | Humphreys, Keith | Brand, Judith | Guénel, Pascal | Truong, Thérèse | Cordina-Duverger, Emilie | Menegaux, Florence | Burwinkel, Barbara | Marme, Frederik | Yang, Rongxi | Surowy, Harald | Benitez, Javier | Zamora, M. Pilar | Perez, Jose I. A. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Chenevix-Trench, Georgia | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Marchand, Loic Le | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J. | Martens, John W. M. | Tilanus-Linthorst, Madeleine M. A. | Collée, J. Margriet | Hopper, John L. | Southey, Melissa C. | Tsimiklis, Helen | Apicella, Carmel | Slager, Susan | Toland, Amanda E. | Ambrosone, Christine B. | Yannoukakos, Drakoulis | Giles, Graham G. | Milne, Roger L. | McLean, Catriona | Fasching, Peter A. | Haeberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Swerdlow, Anthony J. | Ashworth, Alan | Orr, Nick | Jones, Michael | Figueroa, Jonine | Garcia-Closas, Montserrat | Brinton, Louise | Lissowska, Jolanta | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Peterlongo, Paolo | Manoukian, Siranoush | Bonanni, Bernardo | Radice, Paolo | Bogdanova, Natalia | Antonenkova, Natalia | Dörk, Thilo | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Devilee, Peter | Seynaeve, Caroline | Van Asperen, Christi J. | Jakubowska, Anna | Lubiński, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Hamann, Ute | Torres, Diana | Schmutzler, Rita K. | Neuhausen, Susan L. | Anton-Culver, Hoda | Kristensen, Vessela N. | Grenaker Alnæs, Grethe I. | Pierce, Brandon L. | Kraft, Peter | Peters, Ulrike | Lindstrom, Sara | Seminara, Daniela | Burgess, Stephen | Ahsan, Habibul | Whittemore, Alice S. | John, Esther M. | Gammon, Marilie D. | Malone, Kathleen E. | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Healey, Catherine S. | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Álvarez, Nuria | Herrero, Daniel | Pharoah, Paul D. P. | Simard, Jacques | Hall, Per | Hunter, David J. | Easton, Douglas F. | Zheng, Wei
Background:
Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear.
Methods:
We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control subjects, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control subjects.
Results:
The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor–positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5×10–8.
Conclusions:
Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.
doi:10.1093/jnci/djv219
PMCID: PMC4643630  PMID: 26296642
21.  Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer 
Michailidou, Kyriaki | Beesley, Jonathan | Lindstrom, Sara | Canisius, Sander | Dennis, Joe | Lush, Michael | Maranian, Mel J | Bolla, Manjeet K | Wang, Qin | Shah, Mitul | Perkins, Barbara J | Czene, Kamila | Eriksson, Mikael | Darabi, Hatef | Brand, Judith S | Bojesen, Stig E | Nordestgaard, Børge G | Flyger, Henrik | Nielsen, Sune F | Rahman, Nazneen | Turnbull, Clare | Fletcher, Olivia | Peto, Julian | Gibson, Lorna | dos-Santos-Silva, Isabel | Chang-Claude, Jenny | Flesch-Janys, Dieter | Rudolph, Anja | Eilber, Ursula | Behrens, Sabine | Nevanlinna, Heli | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Khan, Sofia | Aaltonen, Kirsimari | Ahsan, Habibul | Kibriya, Muhammad G | Whittemore, Alice S | John, Esther M | Malone, Kathleen E | Gammon, Marilie D | Santella, Regina M | Ursin, Giske | Makalic, Enes | Schmidt, Daniel F | Casey, Graham | Hunter, David J | Gapstur, Susan M | Gaudet, Mia M | Diver, W Ryan | Haiman, Christopher A | Schumacher, Fredrick | Henderson, Brian E | Le Marchand, Loic | Berg, Christine D | Chanock, Stephen | Figueroa, Jonine | Hoover, Robert N | Lambrechts, Diether | Neven, Patrick | Wildiers, Hans | van Limbergen, Erik | Schmidt, Marjanka K | Broeks, Annegien | Verhoef, Senno | Cornelissen, Sten | Couch, Fergus J | Olson, Janet E | Hallberg, Emily | Vachon, Celine | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel A | van der Luijt, Rob B | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Kang, Daehee | Choi, Ji-Yeob | Park, Sue K | Yoo, Keun-Young | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Guénel, Pascal | Truong, Thérèse | Mulot, Claire | Sanchez, Marie | Burwinkel, Barbara | Marme, Frederik | Surowy, Harald | Sohn, Christof | Wu, Anna H | Tseng, Chiu-chen | Van Den Berg, David | Stram, Daniel O | González-Neira, Anna | Benitez, Javier | Zamora, M Pilar | Perez, Jose Ignacio Arias | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Cox, Angela | Cross, Simon S | Reed, Malcolm WR | Andrulis, Irene L | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Lindblom, Annika | Margolin, Sara | Teo, Soo Hwang | Yip, Cheng Har | Taib, Nur Aishah Mohd | TAN, Gie-Hooi | Hooning, Maartje J | Hollestelle, Antoinette | Martens, John WM | Collée, J Margriet | Blot, William | Signorello, Lisa B | Cai, Qiuyin | Hopper, John L | Southey, Melissa C | Tsimiklis, Helen | Apicella, Carmel | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Hou, Ming-Feng | Kristensen, Vessela N | Nord, Silje | Alnaes, Grethe I Grenaker | Giles, Graham G | Milne, Roger L | McLean, Catriona | Canzian, Federico | Trichopoulos, Dmitrios | Peeters, Petra | Lund, Eiliv | Sund, Malin | Khaw, Kay-Tee | Gunter, Marc J | Palli, Domenico | Mortensen, Lotte Maxild | Dossus, Laure | Huerta, Jose-Maria | Meindl, Alfons | Schmutzler, Rita K | Sutter, Christian | Yang, Rongxi | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Hartman, Mikael | Miao, Hui | Chia, Kee Seng | Chan, Ching Wan | Fasching, Peter A | Hein, Alexander | Beckmann, Matthias W | Haeberle, Lothar | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Ashworth, Alan | Orr, Nick | Schoemaker, Minouk J | Swerdlow, Anthony J | Brinton, Louise | Garcia-Closas, Montserrat | Zheng, Wei | Halverson, Sandra L | Shrubsole, Martha | Long, Jirong | Goldberg, Mark S | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Brauch, Hiltrud | Hamann, Ute | Brüning, Thomas | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Bernard, Loris | Bogdanova, Natalia V | Dörk, Thilo | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Devilee, Peter | Tollenaar, Robert AEM | Seynaeve, Caroline | Van Asperen, Christi J | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Huzarski, Tomasz | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Slager, Susan | Toland, Amanda E | Ambrosone, Christine B | Yannoukakos, Drakoulis | Kabisch, Maria | Torres, Diana | Neuhausen, Susan L | Anton-Culver, Hoda | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Healey, Catherine S | Tessier, Daniel C | Vincent, Daniel | Bacot, Francois | Pita, Guillermo | Alonso, M Rosario | Álvarez, Nuria | Herrero, Daniel | Simard, Jacques | Pharoah, Paul PDP | Kraft, Peter | Dunning, Alison M | Chenevix-Trench, Georgia | Hall, Per | Easton, Douglas F
Nature genetics  2015;47(4):373-380.
Genome wide association studies (GWAS) and large scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ~14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS comprising of 15,748 breast cancer cases and 18,084 controls, and 46,785 cases and 42,892 controls from 41 studies genotyped on a 200K custom array (iCOGS). Analyses were restricted to women of European ancestry. Genotypes for more than 11M SNPs were generated by imputation using the 1000 Genomes Project reference panel. We identified 15 novel loci associated with breast cancer at P<5×10−8. Combining association analysis with ChIP-Seq data in mammary cell lines and ChIA-PET chromatin interaction data in ENCODE, we identified likely target genes in two regions: SETBP1 on 18q12.3 and RNF115 and PDZK1 on 1q21.1. One association appears to be driven by an amino-acid substitution in EXO1.
doi:10.1038/ng.3242
PMCID: PMC4549775  PMID: 25751625
22.  Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants 
Mavaddat, Nasim | Pharoah, Paul D. P. | Michailidou, Kyriaki | Tyrer, Jonathan | Brook, Mark N. | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Dunning, Alison M. | Shah, Mitul | Luben, Robert | Brown, Judith | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Peto, Julian | dos-Santos-Silva, Isabel | Dudbridge, Frank | Johnson, Nichola | Schmidt, Marjanka K. | Broeks, Annegien | Verhoef, Senno | Rutgers, Emiel J. | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Schoemaker, Minouk J. | Figueroa, Jonine | Chanock, Stephen J. | Brinton, Louise | Lissowska, Jolanta | Couch, Fergus J. | Olson, Janet E. | Vachon, Celine | Pankratz, Vernon S. | Lambrechts, Diether | Wildiers, Hans | Van Ongeval, Chantal | van Limbergen, Erik | Kristensen, Vessela | Grenaker Alnæs, Grethe | Nord, Silje | Borresen-Dale, Anne-Lise | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Fasching, Peter A. | Haeberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Burwinkel, Barbara | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Trentham-Dietz, Amy | Newcomb, Polly | Titus, Linda | Egan, Kathleen M. | Hunter, David J. | Lindstrom, Sara | Tamimi, Rulla M. | Kraft, Peter | Rahman, Nazneen | Turnbull, Clare | Renwick, Anthony | Seal, Sheila | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Benitez, Javier | Pilar Zamora, M. | Arias Perez, Jose Ignacio | Menéndez, Primitiva | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Dörk, Thilo | Anton-Culver, Hoda | Neuhausen, Susan L. | Ziogas, Argyrios | Bernstein, Leslie | Devilee, Peter | Tollenaar, Robert A. E. M. | Seynaeve, Caroline | van Asperen, Christi J. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Khusnutdinova, Elza | Bermisheva, Marina | Prokofyeva, Darya | Takhirova, Zalina | Meindl, Alfons | Schmutzler, Rita K. | Sutter, Christian | Yang, Rongxi | Schürmann, Peter | Bremer, Michael | Christiansen, Hans | Park-Simon, Tjoung-Won | Hillemanns, Peter | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Sanchez, Marie | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Pensotti, Valeria | Hopper, John L. | Tsimiklis, Helen | Apicella, Carmel | Southey, Melissa C. | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Sigurdson, Alice J. | Doody, Michele M. | Hamann, Ute | Torres, Diana | Ulmer, Hans-Ulrich | Försti, Asta | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Marie Mulligan, Anna | Chenevix-Trench, Georgia | Balleine, Rosemary | Giles, Graham G. | Milne, Roger L. | McLean, Catriona | Lindblom, Annika | Margolin, Sara | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Eilber, Ursula | Wang-Gohrke, Shan | Hooning, Maartje J. | Hollestelle, Antoinette | van den Ouweland, Ans M. W. | Koppert, Linetta B. | Carpenter, Jane | Clarke, Christine | Scott, Rodney | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Brenner, Hermann | Arndt, Volker | Stegmaier, Christa | Karina Dieffenbach, Aida | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Offit, Kenneth | Vijai, Joseph | Robson, Mark | Rau-Murthy, Rohini | Dwek, Miriam | Swann, Ruth | Annie Perkins, Katherine | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Eccles, Diana M. | Tapper, William J. | Rafiq, Sajjad | John, Esther M. | Whittemore, Alice S. | Slager, Susan | Yannoukakos, Drakoulis | Toland, Amanda E. | Yao, Song | Zheng, Wei | Halverson, Sandra L. | González-Neira, Anna | Pita, Guillermo | Rosario Alonso, M. | Álvarez, Nuria | Herrero, Daniel | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Healey, Catherine S. | Simard, Jacques | Hall, Per | Easton, Douglas F. | Garcia-Closas, Montserrat
Background:
Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking.
Methods:
We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates.
Results:
There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer.
Conclusions:
The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
doi:10.1093/jnci/djv036
PMCID: PMC4754625  PMID: 25855707
23.  Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia 
Spurdle, Amanda B | Couch, Fergus J | Parsons, Michael T | McGuffog, Lesley | Barrowdale, Daniel | Bolla, Manjeet K | Wang, Qin | Healey, Sue | Schmutzler, Rita Katharina | Wappenschmidt, Barbara | Rhiem, Kerstin | Hahnen, Eric | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Plendl, Hansjoerg | Niederacher, Dieter | Sutter, Christian | Wang-Gohrke, Shan | Steinemann, Doris | Preisler-Adams, Sabine | Kast, Karin | Varon-Mateeva, Raymonda | Ellis, Steve | Frost, Debra | Platte, Radka | Perkins, Jo | Evans, D Gareth | Izatt, Louise | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Cole, Trevor | Scuvera, Giulietta | Manoukian, Siranoush | Bonanni, Bernardo | Mariette, Frederique | Fortuzzi, Stefano | Viel, Alessandra | Pasini, Barbara | Papi, Laura | Varesco, Liliana | Balleine, Rosemary | Nathanson, Katherine L | Domchek, Susan M | Offitt, Kenneth | Jakubowska, Anna | Lindor, Noralane | Thomassen, Mads | Jensen, Uffe Birk | Rantala, Johanna | Borg, Åke | Andrulis, Irene L | Miron, Alexander | Hansen, Thomas VO | Caldes, Trinidad | Neuhausen, Susan L | Toland, Amanda E | Nevanlinna, Heli | Montagna, Marco | Garber, Judy | Godwin, Andrew K | Osorio, Ana | Factor, Rachel E | Terry, Mary B | Rebbeck, Timothy R | Karlan, Beth Y | Southey, Melissa | Rashid, Muhammad Usman | Tung, Nadine | Pharoah, Paul DP | Blows, Fiona M | Dunning, Alison M | Provenzano, Elena | Hall, Per | Czene, Kamila | Schmidt, Marjanka K | Broeks, Annegien | Cornelissen, Sten | Verhoef, Senno | Fasching, Peter A | Beckmann, Matthias W | Ekici, Arif B | Slamon, Dennis J | Bojesen, Stig E | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Chang-Claude, Jenny | Flesch-Janys, Dieter | Rudolph, Anja | Seibold, Petra | Aittomäki, Kristiina | Muranen, Taru A | Heikkilä, Päivi | Blomqvist, Carl | Figueroa, Jonine | Chanock, Stephen J | Brinton, Louise | Lissowska, Jolanta | Olson, Janet E | Pankratz, Vernon S | John, Esther M | Whittemore, Alice S | West, Dee W | Hamann, Ute | Torres, Diana | Ulmer, Hans Ulrich | Rüdiger, Thomas | Devilee, Peter | Tollenaar, Robert AEM | Seynaeve, Caroline | Van Asperen, Christi J | Eccles, Diana M | Tapper, William J | Durcan, Lorraine | Jones, Louise | Peto, Julian | dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Dwek, Miriam | Swann, Ruth | Bane, Anita L | Glendon, Gord | Mulligan, Anna M | Giles, Graham G | Milne, Roger L | Baglietto, Laura | McLean, Catriona | Carpenter, Jane | Clarke, Christine | Scott, Rodney | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Cox, Angela | Cross, Simon S | Reed, Malcolm WR | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Gronwald, Jacek | Dörk, Thilo | Bogdanova, Natalia | Park-Simon, Tjoung-Won | Hillemanns, Peter | Haiman, Christopher A | Henderson, Brian E | Schumacher, Fredrick | Le Marchand, Loic | Burwinkel, Barbara | Marme, Frederik | Surovy, Harald | Yang, Rongxi | Anton-Culver, Hoda | Ziogas, Argyrios | Hooning, Maartje J | Collée, J Margriet | Martens, John WM | Tilanus-Linthorst, Madeleine MA | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volke | Stegmaier, Christa | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Lindblom, Annika | Margolin, Sara | Joseph, Vijai | Robson, Mark | Rau-Murthy, Rohini | González-Neira, Anna | Arias, José Ignacio | Zamora, Pilar | Benítez, Javier | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Peterlongo, Paolo | Zaffaroni, Daniela | Barile, Monica | Capra, Fabio | Radice, Paolo | Teo, Soo H | Easton, Douglas F | Antoniou, Antonis C | Chenevix-Trench, Georgia | Goldgar, David E
Breast Cancer Research : BCR  2014;16(6):3419.
Introduction
The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling.
Methods
Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach.
Results
ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)).
Conclusions
These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0474-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-014-0474-y
PMCID: PMC4352262  PMID: 25857409
24.  Genome-wide association studies identify four ER negative–specific breast cancer risk loci 
Garcia-Closas, Montserrat | Couch, Fergus J | Lindstrom, Sara | Michailidou, Kyriaki | Schmidt, Marjanka K | Brook, Mark N | orr, Nick | Rhie, Suhn Kyong | Riboli, Elio | Feigelson, Heather s | Le Marchand, Loic | Buring, Julie E | Eccles, Diana | Miron, Penelope | Fasching, Peter A | Brauch, Hiltrud | Chang-Claude, Jenny | Carpenter, Jane | Godwin, Andrew K | Nevanlinna, Heli | Giles, Graham G | Cox, Angela | Hopper, John L | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | Dicks, Ed | Howat, Will J | Schoof, Nils | Bojesen, Stig E | Lambrechts, Diether | Broeks, Annegien | Andrulis, Irene L | Guénel, Pascal | Burwinkel, Barbara | Sawyer, Elinor J | Hollestelle, Antoinette | Fletcher, Olivia | Winqvist, Robert | Brenner, Hermann | Mannermaa, Arto | Hamann, Ute | Meindl, Alfons | Lindblom, Annika | Zheng, Wei | Devillee, Peter | Goldberg, Mark S | Lubinski, Jan | Kristensen, Vessela | Swerdlow, Anthony | Anton-Culver, Hoda | Dörk, Thilo | Muir, Kenneth | Matsuo, Keitaro | Wu, Anna H | Radice, Paolo | Teo, Soo Hwang | Shu, Xiao-Ou | Blot, William | Kang, Daehee | Hartman, Mikael | Sangrajrang, Suleeporn | Shen, Chen-Yang | Southey, Melissa C | Park, Daniel J | Hammet, Fleur | Stone, Jennifer | Veer, Laura J Van’t | Rutgers, Emiel J | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Peto, Julian | Schrauder, Michael G | Ekici, Arif B | Beckmann, Matthias W | Silva, Isabel dos Santos | Johnson, Nichola | Warren, Helen | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Marme, Federick | Schneeweiss, Andreas | Sohn, Christof | Truong, Therese | Laurent-Puig, Pierre | Kerbrat, Pierre | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Milne, Roger L | Perez, Jose Ignacio Arias | Menéndez, Primitiva | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Lichtner, Peter | Lochmann, Magdalena | Justenhoven, Christina | Ko, Yon-Dschun | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Greco, Dario | Heikkinen, Tuomas | Ito, Hidemi | Iwata, Hiroji | Yatabe, Yasushi | Antonenkova, Natalia N | Margolin, Sara | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Balleine, Rosemary | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O | Neven, Patrick | Dieudonné, Anne-Sophie | Leunen, Karin | Rudolph, Anja | Nickels, Stefan | Flesch-Janys, Dieter | Peterlongo, Paolo | Peissel, Bernard | Bernard, Loris | Olson, Janet E | Wang, Xianshu | Stevens, Kristen | Severi, Gianluca | Baglietto, Laura | Mclean, Catriona | Coetzee, Gerhard A | Feng, Ye | Henderson, Brian E | Schumacher, Fredrick | Bogdanova, Natalia V | Labrèche, France | Dumont, Martine | Yip, Cheng Har | Taib, Nur Aishah Mohd | Cheng, Ching-Yu | Shrubsole, Martha | Long, Jirong | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Tollenaar, Robertus A E M | Seynaeve, Caroline M | Kriege, Mieke | Hooning, Maartje J | Van den Ouweland, Ans M W | Van Deurzen, Carolien H M | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Balasubramanian, Sabapathy P | Cross, Simon S | Reed, Malcolm W R | Signorello, Lisa | Cai, Qiuyin | Shah, Mitul | Miao, Hui | Chan, Ching Wan | Chia, Kee Seng | Jakubowska, Anna | Jaworska, Katarzyna | Durda, Katarzyna | Hsiung, Chia-Ni | Wu, Pei-Ei | Yu, Jyh-Cherng | Ashworth, Alan | Jones, Michael | Tessier, Daniel C | González-Neira, Anna | Pita, Guillermo | Alonso, M Rosario | Vincent, Daniel | Bacot, Francois | Ambrosone, Christine B | Bandera, Elisa V | John, Esther M | Chen, Gary K | Hu, Jennifer J | Rodriguez-gil, Jorge L | Bernstein, Leslie | Press, Michael F | Ziegler, Regina G | Millikan, Robert M | Deming-Halverson, Sandra L | Nyante, Sarah | Ingles, Sue A | Waisfisz, Quinten | Tsimiklis, Helen | Makalic, Enes | Schmidt, Daniel | Bui, Minh | Gibson, Lorna | Müller-Myhsok, Bertram | Schmutzler, Rita K | Hein, Rebecca | Dahmen, Norbert | Beckmann, Lars | Aaltonen, Kirsimari | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Turnbull, Clare | Rahman, Nazneen | Meijers-Heijboer, Hanne | Uitterlinden, Andre G | Rivadeneira, Fernando | Olswold, Curtis | Slager, Susan | Pilarski, Robert | Ademuyiwa, Foluso | Konstantopoulou, Irene | Martin, Nicholas G | Montgomery, Grant W | Slamon, Dennis J | Rauh, Claudia | Lux, Michael P | Jud, Sebastian M | Bruning, Thomas | Weaver, Joellen | Sharma, Priyanka | Pathak, Harsh | Tapper, Will | Gerty, Sue | Durcan, Lorraine | Trichopoulos, Dimitrios | Tumino, Rosario | Peeters, Petra H | Kaaks, Rudolf | Campa, Daniele | Canzian, Federico | Weiderpass, Elisabete | Johansson, Mattias | Khaw, Kay-Tee | Travis, Ruth | Clavel-Chapelon, Françoise | Kolonel, Laurence N | Chen, Constance | Beck, Andy | Hankinson, Susan E | Berg, Christine D | Hoover, Robert N | Lissowska, Jolanta | Figueroa, Jonine D | Chasman, Daniel I | Gaudet, Mia M | Diver, W Ryan | Willett, Walter C | Hunter, David J | Simard, Jacques | Benitez, Javier | Dunning, Alison M | Sherman, Mark E | Chenevix-Trench, Georgia | Chanock, Stephen J | Hall, Per | Pharoah, Paul D P | Vachon, Celine | Easton, Douglas F | Haiman, Christopher A | Kraft, Peter
Nature genetics  2013;45(4):392-398e2.
Estrogen receptor (ER)-negative tumors represent 20–30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry1. The etiology2 and clinical behavior3 of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition4. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10−12 and LGR6, P = 1.4 × 10−8), 2p24.1 (P = 4.6 × 10−8) and 16q12.2 (FTO, P = 4.0 × 10−8), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
doi:10.1038/ng.2561
PMCID: PMC3771695  PMID: 23535733
25.  Associations of Breast Cancer Risk Factors With Tumor Subtypes: A Pooled Analysis From the Breast Cancer Association Consortium Studies 
Yang, Xiaohong R. | Chang-Claude, Jenny | Goode, Ellen L. | Couch, Fergus J. | Nevanlinna, Heli | Milne, Roger L. | Gaudet, Mia | Schmidt, Marjanka K. | Broeks, Annegien | Cox, Angela | Fasching, Peter A. | Hein, Rebecca | Spurdle, Amanda B. | Blows, Fiona | Driver, Kristy | Flesch-Janys, Dieter | Heinz, Judith | Sinn, Peter | Vrieling, Alina | Heikkinen, Tuomas | Aittomäki, Kristiina | Heikkilä, Päivi | Blomqvist, Carl | Lissowska, Jolanta | Peplonska, Beata | Chanock, Stephen | Figueroa, Jonine | Brinton, Louise | Hall, Per | Czene, Kamila | Humphreys, Keith | Darabi, Hatef | Liu, Jianjun | Van ‘t Veer, Laura J. | van Leeuwen, Flora E. | Andrulis, Irene L. | Glendon, Gord | Knight, Julia A. | Mulligan, Anna Marie | O’Malley, Frances P. | Weerasooriya, Nayana | John, Esther M. | Beckmann, Matthias W. | Hartmann, Arndt | Weihbrecht, Sebastian B. | Wachter, David L. | Jud, Sebastian M. | Loehberg, Christian R. | Baglietto, Laura | English, Dallas R. | Giles, Graham G. | McLean, Catriona A. | Severi, Gianluca | Lambrechts, Diether | Vandorpe, Thijs | Weltens, Caroline | Paridaens, Robert | Smeets, Ann | Neven, Patrick | Wildiers, Hans | Wang, Xianshu | Olson, Janet E. | Cafourek, Victoria | Fredericksen, Zachary | Kosel, Matthew | Vachon, Celine | Cramp, Helen E. | Connley, Daniel | Cross, Simon S. | Balasubramanian, Sabapathy P. | Reed, Malcolm W. R. | Dörk, Thilo | Bremer, Michael | Meyer, Andreas | Karstens, Johann H. | Ay, Aysun | Park-Simon, Tjoung-Won | Hillemanns, Peter | Arias Pérez, Jose Ignacio | Rodríguez, Primitiva Menéndez | Zamora, Pilar | Benítez, Javier | Ko, Yon-Dschun | Fischer, Hans-Peter | Hamann, Ute | Pesch, Beate | Brüning, Thomas | Justenhoven, Christina | Brauch, Hiltrud | Eccles, Diana M. | Tapper, William J. | Gerty, Sue M. | Sawyer, Elinor J. | Tomlinson, Ian P. | Jones, Angela | Kerin, Michael | Miller, Nicola | McInerney, Niall | Anton-Culver, Hoda | Ziogas, Argyrios | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Yang, Show-Lin | Yu, Jyh-Cherng | Chen, Shou-Tung | Hsu, Giu-Cheng | Haiman, Christopher A. | Henderson, Brian E. | Le Marchand, Loic | Kolonel, Laurence N. | Lindblom, Annika | Margolin, Sara | Jakubowska, Anna | Lubiński, Jan | Huzarski, Tomasz | Byrski, Tomasz | Górski, Bohdan | Gronwald, Jacek | Hooning, Maartje J. | Hollestelle, Antoinette | van den Ouweland, Ans M. W. | Jager, Agnes | Kriege, Mieke | Tilanus-Linthorst, Madeleine M. A. | Collée, Margriet | Wang-Gohrke, Shan | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Mononen, Kari | Grip, Mervi | Hirvikoski, Pasi | Winqvist, Robert | Mannermaa, Arto | Kosma, Veli-Matti | Kauppinen, Jaana | Kataja, Vesa | Auvinen, Päivi | Soini, Ylermi | Sironen, Reijo | Bojesen, Stig E. | Dynnes Ørsted, David | Kaur-Knudsen, Diljit | Flyger, Henrik | Nordestgaard, Børge G. | Holland, Helene | Chenevix-Trench, Georgia | Manoukian, Siranoush | Barile, Monica | Radice, Paolo | Hankinson, Susan E. | Hunter, David J. | Tamimi, Rulla | Sangrajrang, Suleeporn | Brennan, Paul | McKay, James | Odefrey, Fabrice | Gaborieau, Valerie | Devilee, Peter | Huijts, P.E.A. | Tollenaar, RAEM. | Seynaeve, C. | Dite, Gillian S. | Apicella, Carmel | Hopper, John L. | Hammet, Fleur | Tsimiklis, Helen | Smith, Letitia D. | Southey, Melissa C. | Humphreys, Manjeet K. | Easton, Douglas | Pharoah, Paul | Sherman, Mark E. | Garcia-Closas, Montserrat
Background
Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.
Methods
We pooled tumor marker and epidemiological risk factor data from 35 568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case–case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case–control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided.
Results
In case–case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR− than PR+ tumors (P = .001). Nulliparity (P = 3 × 10−6) and increasing age at first birth (P = 2 × 10−9) were less frequent in ER− than in ER+ tumors. Obesity (body mass index [BMI] ≥ 30 kg/m2) in younger women (≤50 years) was more frequent in ER−/PR− than in ER+/PR+ tumors (P = 1 × 10−7), whereas obesity in older women (>50 years) was less frequent in PR− than in PR+ tumors (P = 6 × 10−4). The triple-negative (ER−/PR−/HER2−) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6+ and/or epidermal growth factor receptor [EGFR]+) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case–control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER+ or PR+ tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors.
Conclusions
This study shows that reproductive factors and BMI are most clearly associated with hormone receptor–positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.
doi:10.1093/jnci/djq526
PMCID: PMC3107570  PMID: 21191117

Results 1-25 (125)