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1.  Anti-Müllerian hormone serum concentrations of women with germline BRCA1 or BRCA2 mutations 
Human Reproduction (Oxford, England)  2016;31(5):1126-1132.
STUDY QUESTION
Do women with BRCA1 or BRCA2 mutations have reduced ovarian reserve, as measured by circulating anti-Müllerian hormone (AMH) concentration?
SUMMARY ANSWER
Women with a germline mutation in BRCA1 have reduced ovarian reserve as measured by AMH.
WHAT IS KNOWN ALREADY
The DNA repair enzymes encoded by BRCA1 and BRCA2 are implicated in reproductive aging. Circulating AMH is a biomarker of ovarian reserve and hence reproductive lifespan.
STUDY DESIGN, SIZE, DURATION
This was a cross-sectional study of AMH concentrations of 693 women at the time of enrolment into the Kathleen Cuningham Foundation Consortium for research in the Familial Breast Cancer (kConFab) cohort study (recruitment from 19 August 1997 until 18 September 2012). AMH was measured on stored plasma samples between November 2014 and January 2015 using an electrochemiluminescence immunoassay platform.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Eligible women were from families segregating BRCA1 or BRCA2 mutations and had known mutation status. Participants were aged 25–45 years, had no personal history of cancer, retained both ovaries and were not pregnant or breastfeeding at the time of plasma storage. Circulating AMH was measured for 172 carriers and 216 non-carriers from families carrying BRCA1 mutations, and 147 carriers and 158 non-carriers from families carrying BRCA2 mutations. Associations between plasma AMH concentration and carrier status were tested by linear regression, adjusted for age at plasma storage, oral contraceptive use, body mass index and cigarette smoking.
MAIN RESULTS AND THE ROLE OF CHANCE
Mean AMH concentration was negatively associated with age (P < 0.001). Mutation carriers were younger at blood draw than non-carriers (P ≤ 0.031). BRCA1 mutation carriers had, on average, 25% (95% CI: 5%–41%, P = 0.02) lower AMH concentrations than non-carriers and were more likely to have AMH concentrations in the lowest quartile for age (OR 1.84, 95% CI: 1.11–303, P = 0.02). There was no evidence of an association between AMH concentration and BRCA2 mutation status (P = 0.94).
LIMITATIONS, REASONS FOR CAUTION
AMH does not directly measure the primordial follicle pool. The clinical implications of the lower AMH concentrations seen in BRCA1 mutation carriers cannot be assessed by this study design.
WIDER IMPLICATIONS OF THE FINDINGS
Women with a germline mutation in BRCA1 may have reduced ovarian reserve. This is consistent with other smaller studies in the literature and has potential implications for fertility and reproductive lifespan.
STUDY FUNDING/COMPETING INTEREST(S)
kConFab is supported by a grant from the Australian National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. K.A.P. is an Australian National Breast Cancer Foundation Practitioner Fellow. J.L.H. is a NHMRC Senior Principal Research Fellow. M.H. is a NHMRC Practitioner Fellow. R.A.A. reports personal fees from Roche Diagnostics & Beckman Coulter outside the submitted work and C.S. reports other earnings from Melbourne IVF outside the submitted work. The remaining authors have nothing to declare and no conflicts of interest.
doi:10.1093/humrep/dew044
PMCID: PMC4840025  PMID: 27094481
BRCA1; BRCA2; anti-Müllerian hormone; ovarian reserve; fertility; DNA repair; reproduction
2.  Psychosocial Factors and Survival of Young Women With Breast Cancer: A Population-Based Prospective Cohort Study 
Journal of Clinical Oncology  2008;26(28):4666-4671.
Purpose
Most women with early-stage breast cancer believe that psychosocial factors are an important influence over whether their cancer will recur. Studies of the issue have produced conflicting results.
Patients and Methods
A population-based sample of 708 Australian women diagnosed before age 60 years with nonmetastatic breast cancer was observed for a median of 8.2 years. Depression and anxiety, coping style, and social support were assessed at a median of 11 months after diagnosis. Hazard ratios for distant disease-free survival (DDFS) and overall survival (OS) associated with psychosocial factors were estimated separately using Cox proportional hazards survival models, with and without adjustment for known prognostic factors.
Results
Distant recurrence occurred in 209 (33%) of 638 assessable patients, and 170 (24%) of 708 patients died during the follow-up period. There were no statistically significant associations between any of the measured psychosocial factors and DDFS or OS from the adjusted analyses. From unadjusted analyses, associations between greater anxious preoccupation and poorer DDFS and OS were observed (P = .02). These associations were no longer evident after adjustment for established prognostic factors; greater anxious preoccupation was associated with younger age at diagnosis (P = .03), higher tumor grade (P = .02), and greater number of involved axillary nodes (P = .008).
Conclusion
The findings do not support the measured psychosocial factors being an important influence on breast cancer outcomes. Interventions for adverse psychosocial factors are warranted to improve quality of life but should not be expected to improve survival.
doi:10.1200/JCO.2007.14.8718
PMCID: PMC2653129  PMID: 18824713
3.  Tamoxifen and Risk of Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers 
Journal of Clinical Oncology  2013;31(25):3091-3099.
Purpose
To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers.
Methods
Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral BC since 1970 and no other invasive cancer or tamoxifen use before first BC. Hazard ratios (HRs) for CBC associated with tamoxifen use were estimated using Cox regression, adjusting for year and age of diagnosis, country, and bilateral oophorectomy and censoring at contralateral mastectomy, death, or loss to follow-up.
Results
Of 1,583 BRCA1 and 881 BRCA2 mutation carriers, 383 (24%) and 454 (52%), respectively, took tamoxifen after first BC diagnosis. There were 520 CBCs over 20,104 person-years of observation. The adjusted HR estimates were 0.38 (95% CI, 0.27 to 0.55) and 0.33 (95% CI, 0.22 to 0.50) for BRCA1 and BRCA2 mutation carriers, respectively. After left truncating at recruitment to the cohort, adjusted HR estimates were 0.58 (95% CI, 0.29 to 1.13) and 0.48 (95% CI, 0.22 to 1.05) based on 657 BRCA1 and 426 BRCA2 mutation carriers with 100 CBCs over 4,392 person-years of prospective follow-up. HRs did not differ by estrogen receptor status of the first BC (missing for 56% of cases).
Conclusion
This study provides evidence that tamoxifen use is associated with a reduction in CBC risk for BRCA1 and BRCA2 mutation carriers. Further follow-up of these cohorts will provide increased statistical power for future prospective analyses.
doi:10.1200/JCO.2012.47.8313
PMCID: PMC3753701  PMID: 23918944
4.  An investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors 
Rudolph, Anja | Milne, Roger L. | Truong, Thérèse | Knight, Julia A. | Seibold, Petra | Flesch-Janys, Dieter | Behrens, Sabine | Eilber, Ursula | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Dunning, Alison M. | Shah, Mitul | Munday, Hannah R. | Darabi, Hatef | Eriksson, Mikael | Brand, Judith S. | Olson, Janet | Vachon, Celine M. | Hallberg, Emily | Castelao, J. Esteban | Carracedo, Angel | Torres, Maria | Li, Jingmei | Humphreys, Keith | Cordina-Duverger, Emilie | Menegaux, Florence | Flyger, Henrik | Nordestgaard, Børge G. | Nielsen, Sune F. | Yesilyurt, Betul T. | Floris, Giuseppe | Leunen, Karin | Engelhardt, Ellen G. | Broeks, Annegien | Rutgers, Emiel J. | Glendon, Gord | Mulligan, Anna Marie | Cross, Simon | Reed, Malcolm | Gonzalez-Neira, Anna | Perez, José Ignacio Arias | Provenzano, Elena | Apicella, Carmel | Southey, Melissa C. | Spurdle, Amanda | Investigators, kConFab | Group, AOCS | Häberle, Lothar | Beckmann, Matthias W. | Ekici, Arif B. | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | McLean, Catriona | Baglietto, Laura | Chanock, Stephen J. | Lissowska, Jolanta | Sherman, Mark E. | Brüning, Thomas | Hamann, Ute | Ko, Yon-Dschun | Orr, Nick | Schoemaker, Minouk | Ashworth, Alan | Kosma, Veli-Matti | Kataja, Vesa | Hartikainen, Jaana M. | Mannermaa, Arto | Swerdlow, Anthony | Giles, Graham G. | Brenner, Hermann | Fasching, Peter A. | Chenevix-Trench, Georgia | Hopper, John | Benítez, Javier | Cox, Angela | Andrulis, Irene L. | Lambrechts, Diether | Gago-Dominguez, Manuela | Couch, Fergus | Czene, Kamila | Bojesen, Stig E. | Easton, Doug F. | Schmidt, Marjanka K. | Guénel, Pascal | Hall, Per | Pharoah, Paul D. P. | Garcia-Closas, Montserrat | Chang-Claude, Jenny
A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC.
Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator.
Six SNPs showed interactions with associated p-values (pint) <1.1×10−3. None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women ≥170cm (OR=1.22, p=0.017), but inversely associated with ER-negative BC risk in women <160cm (OR=0.83, p=0.039, pint=1.9×10−4). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR=0.85, p=2.0×10−4), and absent in women who had had just one (OR=0.96, p=0.19, pint = 6.1×10−4). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR=0.93, p=2.8×10−5), but no association was observed in current smokers (OR=1.07, p=0.14, pint = 3.4×10−4).
In conclusion, recently identified breast cancer susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies.
doi:10.1002/ijc.29188
PMCID: PMC4289418  PMID: 25227710
gene-environment interaction; breast cancer; risk factor; genetic susceptibility
5.  Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia 
Berndt, Sonja I. | Camp, Nicola J. | Skibola, Christine F. | Vijai, Joseph | Wang, Zhaoming | Gu, Jian | Nieters, Alexandra | Kelly, Rachel S. | Smedby, Karin E. | Monnereau, Alain | Cozen, Wendy | Cox, Angela | Wang, Sophia S. | Lan, Qing | Teras, Lauren R. | Machado, Moara | Yeager, Meredith | Brooks-Wilson, Angela R. | Hartge, Patricia | Purdue, Mark P. | Birmann, Brenda M. | Vajdic, Claire M. | Cocco, Pierluigi | Zhang, Yawei | Giles, Graham G. | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Montalvan, Rebecca | Burdett, Laurie | Hutchinson, Amy | Ye, Yuanqing | Call, Timothy G. | Shanafelt, Tait D. | Novak, Anne J. | Kay, Neil E. | Liebow, Mark | Cunningham, Julie M. | Allmer, Cristine | Hjalgrim, Henrik | Adami, Hans-Olov | Melbye, Mads | Glimelius, Bengt | Chang, Ellen T. | Glenn, Martha | Curtin, Karen | Cannon-Albright, Lisa A. | Diver, W Ryan | Link, Brian K. | Weiner, George J. | Conde, Lucia | Bracci, Paige M. | Riby, Jacques | Arnett, Donna K. | Zhi, Degui | Leach, Justin M. | Holly, Elizabeth A. | Jackson, Rebecca D. | Tinker, Lesley F. | Benavente, Yolanda | Sala, Núria | Casabonne, Delphine | Becker, Nikolaus | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Chaffee, Kari G. | Achenbach, Sara J. | Vachon, Celine M. | Goldin, Lynn R. | Strom, Sara S. | Leis, Jose F. | Weinberg, J. Brice | Caporaso, Neil E. | Norman, Aaron D. | De Roos, Anneclaire J. | Morton, Lindsay M. | Severson, Richard K. | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Masala, Giovanna | Weiderpass, Elisabete | Chirlaque, María- Dolores | Vermeulen, Roel C. H. | Travis, Ruth C. | Southey, Melissa C. | Milne, Roger L. | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Clavel, Jacqueline | Zheng, Tongzhang | Holford, Theodore R. | Villano, Danylo J. | Maria, Ann | Spinelli, John J. | Gascoyne, Randy D. | Connors, Joseph M. | Bertrand, Kimberly A. | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Ma, Baoshan | Huang, Jinyan | Crouch, Simon | Park, Ju-Hyun | Chatterjee, Nilanjan | North, Kari E. | Snowden, John A. | Wright, Josh | Fraumeni, Joseph F. | Offit, Kenneth | Wu, Xifeng | de Sanjose, Silvia | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature Communications  2016;7:10933.
Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10−11), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10−8) and 3q28 (rs9815073, LPP, P=3.62 × 10−8), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10−11) in the combined analysis. We find suggestive evidence (P<5 × 10−7) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10−8) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10−7). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.
Chronic lymphocytic leukemia is a highly inheritable cancer. Here the authors conduct a metaanalysis of four genome-wide association studies and identify three novel loci located near EOMES, SERPINB6 and LPP associated with risk of this disease.
doi:10.1038/ncomms10933
PMCID: PMC4786871  PMID: 26956414
6.  Genetic predisposition to ductal carcinoma in situ of the breast 
Petridis, Christos | Brook, Mark N. | Shah, Vandna | Kohut, Kelly | Gorman, Patricia | Caneppele, Michele | Levi, Dina | Papouli, Efterpi | Orr, Nick | Cox, Angela | Cross, Simon S. | dos-Santos-Silva, Isabel | Peto, Julian | Swerdlow, Anthony | Schoemaker, Minouk J. | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Michailidou, Kyriaki | Benitez, Javier | González-Neira, Anna | Tessier, Daniel C. | Vincent, Daniel | Li, Jingmei | Figueroa, Jonine | Kristensen, Vessela | Borresen-Dale, Anne-Lise | Soucy, Penny | Simard, Jacques | Milne, Roger L. | Giles, Graham G. | Margolin, Sara | Lindblom, Annika | Brüning, Thomas | Brauch, Hiltrud | Southey, Melissa C. | Hopper, John L. | Dörk, Thilo | Bogdanova, Natalia V. | Kabisch, Maria | Hamann, Ute | Schmutzler, Rita K. | Meindl, Alfons | Brenner, Hermann | Arndt, Volker | Winqvist, Robert | Pylkäs, Katri | Fasching, Peter A. | Beckmann, Matthias W. | Lubinski, Jan | Jakubowska, Anna | Mulligan, Anna Marie | Andrulis, Irene L. | Tollenaar, Rob A. E. M. | Devilee, Peter | Le Marchand, Loic | Haiman, Christopher A. | Mannermaa, Arto | Kosma, Veli-Matti | Radice, Paolo | Peterlongo, Paolo | Marme, Frederik | Burwinkel, Barbara | van Deurzen, Carolien H. M. | Hollestelle, Antoinette | Miller, Nicola | Kerin, Michael J. | Lambrechts, Diether | Floris, Giuseppe | Wesseling, Jelle | Flyger, Henrik | Bojesen, Stig E. | Yao, Song | Ambrosone, Christine B. | Chenevix-Trench, Georgia | Truong, Thérèse | Guénel, Pascal | Rudolph, Anja | Chang-Claude, Jenny | Nevanlinna, Heli | Blomqvist, Carl | Czene, Kamila | Brand, Judith S. | Olson, Janet E. | Couch, Fergus J. | Dunning, Alison M. | Hall, Per | Easton, Douglas F. | Pharoah, Paul D. P. | Pinder, Sarah E. | Schmidt, Marjanka K | Tomlinson, Ian | Roylance, Rebecca | García-Closas, Montserrat | Sawyer, Elinor J.
Background
Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci.
Methods
To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip.
Results
Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing.
Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC.
We found no novel DCIS-specific loci at a genome wide significance level of P < 5.0x10-8.
Conclusion
In conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-016-0675-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-016-0675-7
PMCID: PMC4756509  PMID: 26884359
Ductal carcinoma in situ; Association study; Genetic predisposition; Common variants
7.  Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer 
Kabisch, Maria | Lorenzo Bermejo, Justo | Dünnebier, Thomas | Ying, Shibo | Michailidou, Kyriaki | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | 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 | Peeters, Stephanie | Weltens, Caroline | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Purrington, Kristen | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Peto, Julian | dos-Santos-Silva, Isabel | Johnson, Nichola | Fletcher, Olivia | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Schmidt, Marjanka K. | Broeks, Annegien | Cornelissen, Sten | Hogervorst, Frans B.L. | Li, Jingmei | Brand, Judith S. | Humphreys, Keith | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Sanchez, Marie | Burwinkel, Barbara | Marmé, Frederik | Yang, Rongxi | Bugert, Peter | González-Neira, Anna | Benitez, Javier | Pilar Zamora, M. | Arias Perez, Jose I. | 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 | Haiman, Christopher A. | Schumacher, Fredrick | Henderson, Brian E. | Le Marchand, Loic | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J. | Hollestelle, Antoinette | Kriege, Mieke | Koppert, Linetta B. | Hopper, John L. | Southey, Melissa C. | Tsimiklis, Helen | Apicella, Carmel | Slettedahl, Seth | Toland, Amanda E. | Vachon, Celine | Yannoukakos, Drakoulis | Giles, Graham G. | Milne, Roger L. | McLean, Catriona | Fasching, Peter A. | Ruebner, Matthias | Ekici, Arif B. | Beckmann, Matthias W. | Brenner, Hermann | Dieffenbach, Aida K. | Arndt, Volker | Stegmaier, Christa | Ashworth, Alan | Orr, Nicholas | Schoemaker, Minouk J. | Swerdlow, Anthony | García-Closas, Montserrat | Figueroa, Jonine | Chanock, Stephen J. | Lissowska, Jolanta | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Radice, Paolo | Peterlongo, Paolo | Scuvera, Giulietta | Fortuzzi, Stefano | Bogdanova, Natalia | Dörk, Thilo | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Van Asperen, Christi J. | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Zheng, Wei | Shrubsole, Martha J. | Cai, Qiuyin | Torres, Diana | Anton-Culver, Hoda | Kristensen, Vessela | Bacot, François | Tessier, Daniel C. | Vincent, Daniel | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Simard, Jacques | Chenevix-Trench, Georgia | Hall, Per | Pharoah, Paul D.P. | Dunning, Alison M. | Easton, Douglas F. | Hamann, Ute
Carcinogenesis  2015;36(2):256-271.
Summary
This is the first study investigating the contribution of inherited variants in core genes of the chromosomal passenger complex to breast cancer susceptibility. It was found that several INCENP variants are associated with the risk of ER-negative breast cancer in the European population.
The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk [per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92–0.98, P = 0.007] and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83–0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3ʹ untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00–1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02–1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04–1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated.
doi:10.1093/carcin/bgu326
PMCID: PMC4335262  PMID: 25586992
8.  Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC) 
Jim, Heather S.L. | Lin, Hui-Yi | Tyrer, Jonathan P. | Lawrenson, Kate | Dennis, Joe | Chornokur, Ganna | Chen, Zhihua | Chen, Ann Y. | Permuth-Wey, Jennifer | Aben, Katja KH. | Anton-Culver, Hoda | Antonenkova, Natalia | Bruinsma, Fiona | Bandera, Elisa V. | Bean, Yukie T. | Beckmann, Matthias W. | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bunker, Clareann H. | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chang-Claude, Jenny | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | du Bois, Andreas | Despierre, Evelyn | Sieh, Weiva | Doherty, Jennifer A. | Dörk, Thilo | Dürst, Matthias | Easton, Douglas F. | Eccles, Diana M. | Edwards, Robert P. | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goodman, Marc T. | Gronwald, Jacek | Harter, Philipp | Hasmad, Hanis N. | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A.T. | Hillemanns, Peter | Hogdall, Claus K. | Hogdall, Estrid | Hosono, Satoyo | Iversen, Edwin S. | Jakubowska, Anna | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y. | Kellar, Melissa | Kiemeney, Lambertus A. | Krakstad, Camilla | Kjaer, Susanne K. | Kupryjanczyk, Jolanta | Vierkant, Robert A. | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lim, Boon Kiong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | McNeish, Ian | Menon, Usha | Milne, Roger L. | Modugno, Francesmary | Thomsen, Lotte | Moysich, Kirsten B. | Ness, Roberta B. | Nevanlinna, Heli | Eilber, Ursula | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Palmieri Weber, Rachel | Paul, James | Pearce, Celeste L. | Pejovic, Tanja | Pelttari, Liisa M. | Pike, Malcolm C. | Poole, Elizabeth M. | Schernhammer, Eva | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schwaab, Ira | Shu, Xiao-Ou | Shvetsov, Yurii B. | Siddiqui, Nadeem | Song, Honglin | Southey, Melissa C. | Spiewankiewicz, Beata | Sucheston-Campbell, Lara | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J. | Tangen, Ingvild L. | Tworoger, Shelley S. | van Altena, Anne M. | Vergote, Ignace | Walsh, Christine S. | Wang-Gohrke, Shan | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Wu, Anna H. | Wu, Xifeng | Woo, Yin-Ling | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Amankwah, Ernest | Berchuck, Andrew | Schildkraut, Joellen M. | Kelemen, Linda E. | Ramus, Susan J. | Monteiro, Alvaro N.A. | Goode, Ellen L. | Narod, Steven A. | Gayther, Simon A. | Pharoah, Paul D. P. | Sellers, Thomas A. | Phelan, Catherine M.
Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68–0.90, p = 5.59 × 10−4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.
PMCID: PMC4722961  PMID: 26807442
9.  Epithelial-Mesenchymal Transition (EMT) gene variants and Epithelial Ovarian Cancer (EOC) risk 
Amankwah, Ernest K. | Lin, Hui-Yi | Tyrer, Jonathan P. | Lawrenson, Kate | Dennis, Joe | Chornokur, Ganna | Aben, Katja KH. | Anton-Culver, Hoda | Antonenkova, Natalia | Bruinsma, Fiona | Bandera, Elisa V. | Bean, Yukie T. | Beckmann, Matthias W. | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bunker, Clareann H. | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chen, Zhihua | Chen, Y. Ann | Chang-Claude, Jenny | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | du Bois, Andreas | Despierre, Evelyn | Dicks, Ed | Doherty, Jennifer A. | Dörk, Thilo | Dürst, Matthias | Easton, Douglas F. | Eccles, Diana M. | Edwards, Robert P. | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goodman, Marc T. | Gronwald, Jacek | Harrington, Patricia | Harter, Philipp | Hasmad, Hanis N. | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A.T. | Hillemanns, Peter | Hogdall, Claus K. | Hogdall, Estrid | Hosono, Satoyo | Iversen, Edwin S. | Jakubowska, Anna | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y. | Jim, Heather | Kellar, Melissa | Kiemeney, Lambertus A. | Krakstad, Camilla | Kjaer, Susanne K. | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lim, Boon Kiong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | McNeish, Ian | Menon, Usha | Milne, Roger L. | Modugno, Francesmary | Moysich, Kirsten B. | Ness, Roberta B. | Nevanlinna, Heli | Eilber, Ursula | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Weber, Rachel Palmieri | Paul, James | Pearce, Celeste L. | Pejovic, Tanja | Pelttari, Liisa M. | Permuth-Wey, Jennifer | Pike, Malcolm C. | Poole, Elizabeth M. | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schernhammer, Eva | Schwaab, Ira | Shu, Xiao-Ou | Shvetsov, Yurii B. | Siddiqui, Nadeem | Sieh, Weiva | Song, Honglin | Southey, Melissa C. | Spiewankiewicz, Beata | Sucheston-Campbell, Lara | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J. | Thomsen, Lotte | Tangen, Ingvild L. | Tworoger, Shelley S. | van Altena, Anne M. | Vierkant, Robert A. | Vergote, Ignace | Walsh, Christine S. | Wang-Gohrke, Shan | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Wu, Anna H. | Wu, Xifeng | Woo, Yin-Ling | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Kelemen, Linda E. | Berchuck, Andrew | Schildkraut, Joellen M. | Ramus, Susan J. | Goode, Ellen L. | Monteiro, Alvaro N.A. | Gayther, Simon A. | Narod, Steven A. | Pharoah, Paul D. P. | Sellers, Thomas A. | Phelan, Catherine M.
Genetic epidemiology  2015;39(8):689-697.
Introduction
Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to EOC risk have been based on small sample sizes and none have sought replication in an independent population.
Methods
We screened 1254 SNPs in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (p<0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A p-value <0.05 and a false discovery rate (FDR) <0.2 was considered statistically significant.
Results
In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (OR=1.16, 95%CI=1.07–1.25, p=0.0003, FDR=0.19), while F8 rs7053448 (OR=1.69, 95%CI=1.27–2.24, p=0.0003, FDR=0.12), F8 rs7058826 (OR=1.69, 95%CI=1.27–2.24, p=0.0003, FDR=0.12), and CAPN13 rs1983383 (OR=0.79, 95%CI=0.69–0.90, p=0.0005, FDR=0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements.
Conclusion
These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.
doi:10.1002/gepi.21921
PMCID: PMC4721602  PMID: 26399219
ovarian cancer; epithelial-mesenchymal transition; single nucleotide polymorphisms
10.  Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk 
Lin, Wei-Yu | Camp, Nicola J. | Ghoussaini, Maya | Beesley, Jonathan | Michailidou, Kyriaki | Hopper, John L. | Apicella, Carmel | Southey, Melissa C. | Stone, Jennifer | Schmidt, Marjanka K. | Broeks, Annegien | Van't Veer, Laura J. | Th Rutgers, Emiel J. | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Fasching, Peter A. | Haeberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Peto, Julian | Dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Sawyer, Elinor J. | Cheng, Timothy | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Marmé, Frederik | Surowy, Harald M. | Burwinkel, Barbara | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Mulot, Claire | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, M. Pilar | Arias Perez, Jose Ignacio | Menéndez, Primitiva | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Álvarez, Nuria | Herrero, Daniel | Anton-Culver, Hoda | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Meindl, Alfons | Lichtner, Peter | Schmutzler, Rita K. | Müller-Myhsok, Bertram | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Nevanlinna, Heli | Aittomäki, Kristiina | Blomqvist, Carl | Khan, Sofia | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Horio, Akiyo | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Dörk, Thilo | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Wu, Anna H. | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O. | Neven, Patrick | Wauters, Els | Wildiers, Hans | Lambrechts, Diether | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Bonanni, Bernardo | Couch, Fergus J. | Wang, Xianshu | Vachon, Celine | Purrington, Kristen | Giles, Graham G. | Milne, Roger L. | Mclean, Catriona | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Teo, Soo Hwang | Yip, Cheng Har | Hassan, Norhashimah | Vithana, Eranga Nishanthie | Kristensen, Vessela | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha J. | Long, Jirong | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Van Asperen, Christi J. | García-Closas, Montserrat | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Brand, Judith S. | Hooning, Maartje J. | Hollestelle, Antoinette | Van Den Ouweland, Ans M.W. | Jager, Agnes | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Cross, Simon S. | Reed, Malcolm W. R. | Blot, William | Signorello, Lisa B. | Cai, Qiuyin | Pharoah, Paul D.P. | Perkins, Barbara | Shah, Mitul | Blows, Fiona M. | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Hartman, Mikael | Miao, Hui | Chia, Kee Seng | Putti, Thomas Choudary | Hamann, Ute | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Healey, Catherine S. | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | Mckay, James | Slager, Susan | Toland, Amanda E. | Yannoukakos, Drakoulis | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Ding, Shian-ling | Ashworth, Alan | Jones, Michael | Orr, Nick | Swerdlow, Anthony J | Tsimiklis, Helen | Makalic, Enes | Schmidt, Daniel F. | Bui, Quang M. | Chanock, Stephen J. | Hunter, David J. | Hein, Rebecca | Dahmen, Norbert | Beckmann, Lars | Aaltonen, Kirsimari | Muranen, Taru A. | Heikkinen, Tuomas | Irwanto, Astrid | Rahman, Nazneen | Turnbull, Clare A. | Waisfisz, Quinten | Meijers-Heijboer, Hanne E. J. | Adank, Muriel A. | Van Der Luijt, Rob B. | Hall, Per | Chenevix-Trench, Georgia | Dunning, Alison | Easton, Douglas F. | Cox, Angela
Human Molecular Genetics  2014;24(1):285-298.
Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03–1.07), P = 1 × 10−5. Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10−6), yielding a combined OR (95% CI) of 1.06 (1.04–1.08), P = 1 × 10−9. Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
doi:10.1093/hmg/ddu431
PMCID: PMC4334820  PMID: 25168388
11.  Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium 
Lei, Jieping | Rudolph, Anja | Moysich, Kirsten B. | Behrens, Sabine | Goode, Ellen L. | Bolla, Manjeet K. | Dennis, Joe | Dunning, Alison M. | Easton, Douglas F. | Wang, Qin | Benitez, Javier | Hopper, John L. | Southey, Melissa C. | Schmidt, Marjanka K. | Broeks, Annegien | Fasching, Peter A. | Haeberle, Lothar | Peto, Julian | dos-Santos-Silva, Isabel | Sawyer, Elinor J. | Tomlinson, Ian | Burwinkel, Barbara | Marmé, Frederik | Guénel, Pascal | Truong, Thérèse | Bojesen, Stig E. | Flyger, Henrik | Nielsen, Sune F. | Nordestgaard, Børge G. | González-Neira, Anna | Menéndez, Primitiva | Anton-Culver, Hoda | Neuhausen, Susan L. | Brenner, Hermann | Arndt, Volker | Meindl, Alfons | Schmutzler, Rita K. | Brauch, Hiltrud | Hamann, Ute | Nevanlinna, Heli | Fagerholm, Rainer | Dörk, Thilo | Bogdanova, Natalia V. | Mannermaa, Arto | Hartikainen, Jaana M. | Van Dijck, Laurien | Smeets, Ann | Flesch-Janys, Dieter | Eilber, Ursula | Radice, Paolo | Peterlongo, Paolo | Couch, Fergus J. | Hallberg, Emily | Giles, Graham G. | Milne, Roger L. | Haiman, Christopher A. | Schumacher, Fredrick | Simard, Jacques | Goldberg, Mark S. | Kristensen, Vessela | Borresen-Dale, Anne-Lise | Zheng, Wei | Beeghly-Fadiel, Alicia | Winqvist, Robert | Grip, Mervi | Andrulis, Irene L. | Glendon, Gord | García-Closas, Montserrat | Figueroa, Jonine | Czene, Kamila | Brand, Judith S. | Darabi, Hatef | Eriksson, Mikael | Hall, Per | Li, Jingmei | Cox, Angela | Cross, Simon S. | Pharoah, Paul D. P. | Shah, Mitul | Kabisch, Maria | Torres, Diana | Jakubowska, Anna | Lubinski, Jan | Ademuyiwa, Foluso | Ambrosone, Christine B. | Swerdlow, Anthony | Jones, Michael | Chang-Claude, Jenny
Human Genetics  2015;135:137-154.
Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03–1.08; p value = 1.4 × 10−6). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10−3 and 7.0 × 10−3, respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10−3, 4.5 × 10−4 and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3,IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-015-1616-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s00439-015-1616-8
PMCID: PMC4698282  PMID: 26621531
12.  Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade 
Purrington, Kristen S. | Slettedahl, Seth | Bolla, Manjeet K. | Michailidou, Kyriaki | Czene, Kamila | Nevanlinna, Heli | Bojesen, Stig E. | Andrulis, Irene L. | Cox, Angela | Hall, Per | Carpenter, Jane | Yannoukakos, Drakoulis | Haiman, Christopher A. | Fasching, Peter A. | Mannermaa, Arto | Winqvist, Robert | Brenner, Hermann | Lindblom, Annika | Chenevix-Trench, Georgia | Benitez, Javier | Swerdlow, Anthony | Kristensen, Vessela | Guénel, Pascal | Meindl, Alfons | Darabi, Hatef | Eriksson, Mikael | Fagerholm, Rainer | Aittomäki, Kristiina | Blomqvist, Carl | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Wang, Xianshu | Olswold, Curtis | Olson, Janet E. | Mulligan, Anna Marie | Knight, Julia A. | Tchatchou, Sandrine | Reed, Malcolm W.R. | Cross, Simon S. | Liu, Jianjun | Li, Jingmei | Humphreys, Keith | Clarke, Christine | Scott, Rodney | Fostira, Florentia | Fountzilas, George | Konstantopoulou, Irene | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Ekici, Arif B. | Hartmann, Arndt | Beckmann, Matthias W. | Hartikainen, Jaana M. | Kosma, Veli-Matti | Kataja, Vesa | Jukkola-Vuorinen, Arja | Pylkäs, Katri | Kauppila, Saila | Dieffenbach, Aida Karina | Stegmaier, Christa | Arndt, Volker | Margolin, Sara | Balleine, Rosemary | Arias Perez, Jose Ignacio | Pilar Zamora, M. | Menéndez, Primitiva | Ashworth, Alan | Jones, Michael | Orr, Nick | Arveux, Patrick | Kerbrat, Pierre | Truong, Thérèse | Bugert, Peter | Toland, Amanda E. | Ambrosone, Christine B. | Labrèche, France | Goldberg, Mark S. | Dumont, Martine | Ziogas, Argyrios | Lee, Eunjung | Dite, Gillian S. | Apicella, Carmel | Southey, Melissa C. | Long, Jirong | Shrubsole, Martha | Deming-Halverson, Sandra | Ficarazzi, Filomena | Barile, Monica | Peterlongo, Paolo | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Brüning, Thomas | Ko, Yon-Dschun | Van Deurzen, Carolien H.M. | Martens, John W.M. | Kriege, Mieke | Figueroa, Jonine D. | Chanock, Stephen J. | Lissowska, Jolanta | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Schneeweiss, Andreas | Tapper, William J. | Gerty, Susan M. | Durcan, Lorraine | Mclean, Catriona | Milne, Roger L. | Baglietto, Laura | dos Santos Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Van'T Veer, Laura J. | Cornelissen, Sten | Försti, Asta | Torres, Diana | Rüdiger, Thomas | Rudolph, Anja | Flesch-Janys, Dieter | Nickels, Stefan | Weltens, Caroline | Floris, Giuseppe | Moisse, Matthieu | Dennis, Joe | Wang, Qin | Dunning, Alison M. | Shah, Mitul | Brown, Judith | Simard, Jacques | Anton-Culver, Hoda | Neuhausen, Susan L. | Hopper, John L. | Bogdanova, Natalia | Dörk, Thilo | Zheng, Wei | Radice, Paolo | Jakubowska, Anna | Lubinski, Jan | Devillee, Peter | Brauch, Hiltrud | Hooning, Maartje | García-Closas, Montserrat | Sawyer, Elinor | Burwinkel, Barbara | Marmee, Frederick | Eccles, Diana M. | Giles, Graham G. | Peto, Julian | Schmidt, Marjanka | Broeks, Annegien | Hamann, Ute | Chang-Claude, Jenny | Lambrechts, Diether | Pharoah, Paul D.P. | Easton, Douglas | Pankratz, V. Shane | Slager, Susan | Vachon, Celine M. | Couch, Fergus J.
Human Molecular Genetics  2014;23(22):6034-6046.
Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16–1.33, P = 4.2 × 10−10) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04–1.11, P = 8.7 × 10−6) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07–1.23, P = 7.9 × 10−5) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10−3). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.
doi:10.1093/hmg/ddu300
PMCID: PMC4204763  PMID: 24927736
13.  Confirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer 
Milne, Roger L. | Goode, Ellen L. | García-Closas, Montserrat | Couch, Fergus J. | Severi, Gianluca | Hein, Rebecca | Fredericksen, Zachary | Malats, Núria | Zamora, M. Pilar | Pérez, Jose Ignacio Arias | Benítez, Javier | Dörk, Thilo | Schürmann, Peter | Karstens, Johann H. | Hillemanns, Peter | Cox, Angela | Brock, Ian W. | Elliot, Graeme | Cross, Simon S. | Seal, Sheila | Turnbull, Clare | Renwick, Anthony | Rahman, Nazneen | Shen, Chen-Yang | Yu, Jyh-Cherng | Huang, Chiun-Sheng | Hou, Ming-Feng | Nordestgaard, Børge G. | Bojesen, Stig E. | Lanng, Charlotte | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børrensen-Dale, Anne-Lise | Hopper, John L. | Dite, Gillian S. | Apicella, Carmel | Southey, Melissa C. | Lambrechts, Diether | Yesilyurt, Betül T. | Floris, Giuseppe | Leunen, Karin | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Chang-Claude, Jenny | Wang-Gohrke, Shan | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Barile, Monica | Giles, Graham G. | Baglietto, Laura | John, Esther M. | Miron, Alexander | Chanock, Stephen J. | Lissowska, Jolanta | Sherman, Mark E. | Figueroa, Jonine D. | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Zalutsky, Iosif V. | Rogov, Yuri I. | Fasching, Peter A. | Bayer, Christian M. | Ekici, Arif B. | Beckmann, Matthias W. | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Meindl, Alfons | Heil, Joerg | Bartram, Claus R. | Schmutzler, Rita K. | Thomas, Gilles D. | Hoover, Robert N. | Fletcher, Olivia | Gibson, Lorna J. | Silva, Isabel dos Santos | Peto, Julian | Nickels, Stefan | Flesch-Janys, Dieter | Anton-Culver, Hoda | Ziogas, Argyrios | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Schmidt, Marjanka K. | Broeks, Annegien | Van ‘t Veer, Laura J. | Tollenaar, Rob A.E.M. | Pharoah, Paul D.P. | Dunning, Alison M. | Pooley, Karen A. | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Ahn, Sei-Hyun | Hunter, David J. | Hankinson, Susan E. | Kraft, Peter | Lindstrom, Sara | Chen, Xiaoqing | Beesley, Jonathan | Hamann, Ute | Harth, Volker | Justenhoven, Christina | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Hooning, Maartje | Hollestelle, Antoinette | Oldenburg, Rogier A. | Tilanus-Linthorst, Madeleine | Khusnutdinova, Elza | Bermisheva, Marina | Prokofieva, Darya | Farahtdinova, Albina | Olson, Janet E. | Wang, Xianshu | Humphreys, Manjeet K. | Wang, Qin | Chenevix-Trench, Georgia | Easton, Douglas F.
Background
The single nucleotide polymorphism 5p12-rs10941679has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium.
Methods
Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS) and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression.
Results
For white Europeans, the per-allele odds ratio (OR) associated with 5p12-rs10941679 was 1.11 (95% confidence interval [CI] =1.08–1.14, P=7×10−18) for invasive breast cancer and 1.10 (95%CI=1.01–1.21, P=0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR=1.07, 95%CI=0.99–1.15, P=0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR=1.16, 95%CI=1.12–1.20, P=1×10−18 versus OR=1.03, 95%CI=0.99–1.07, P=0.2 for PR-negative disease; P-heterogeneity=2×10−7); heterogeneity by estrogen receptor status was not observed (P=0.2) once PR status was accounted for. The association was also stronger for lower-grade tumors (per-allele OR [95%CI]=1.20 [1.14–1.25], 1.13 [1.09–1.16] and 1.04 [0.99–1.08] for grade 1, 2 and 3/4, respectively; P–trend=5×10−7).
Conclusion
5p12 is a breast cancer susceptibility locus for PR-positive, lower gradebreast cancer.
Impact
Multi-centre fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants.
doi:10.1158/1055-9965.EPI-11-0569
PMCID: PMC4164116  PMID: 21795498
Breast cancer; SNP; susceptibility; disease subtypes
14.  Tools for translational epigenetic studies involving formalin-fixed paraffin-embedded human tissue: applying the Infinium HumanMethyation450 Beadchip assay to large population-based studies 
BMC Research Notes  2015;8:543.
Background
Large population-based translational epigenetic studies are emerging due to recent technological advances that have made molecular analyses possible. For example, the Infinium HumanMethylation450 Beadchip (HM450K) has enabled studies of genome-wide methylation on a scale not previously possible. However, application of the HM450K to DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour material has been more challenging than application to high quality DNA extracted from blood. To facilitate the application of this assay consistently across a large number of FFPE tumour-enriched DNA samples we have devised a modification to the HM450K protocol for FFPE that includes an additional quality control (QC) checkpoint.
Results
QC checkpoint 3 was designed to assess the presence of DNA after bisulfite conversion and restoration, just prior to application of the HM450K assay. DNA was extracted from 474 archival FFPE breast tumour material. Five samples did not have a detectable amount of DNA with an additional 42 failing to progress past QC checkpoint 3. Genome-wide methylation was measured for the remaining 428 tumour-enriched DNA. Of these, only 4 samples failed our stringent HM450K data criteria thus representing a 99 % success rate. Using prior knowledge about methylation marks associated with breast cancer we further explored the quality of the data. Twenty probes in the BRCA1 promoter region showed increased methylation in triple-negative breast cancers compared to Luminal A, Luminal B and HER2-positive breast cancer subtypes. Validation of this observation in published data from The Cancer Genome Atlas (TCGA) Network (obtained from DNA extracted from fresh frozen tumour samples) confirms the quality of the data obtained from the improved protocol.
Conclusions
The modified protocol is suitable for the analysis of FFPE tumour-enriched DNA and can be systematically applied to hundreds of samples. This protocol will have utility in population-based translational epigenetic studies and is applicable to a wide variety of translated studies interested in analysis of methylation and its role in the predisposition to disease and disease progression.
Electronic supplementary material
The online version of this article (doi:10.1186/s13104-015-1487-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s13104-015-1487-z
PMCID: PMC4595238  PMID: 26438025
Population-based translational epigenetic studies; Formalin-fixed paraffin-embedded; DNA methylation; Epigenetics; HM450K beadchip; Breast tumour subtype; BRCA1
15.  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
16.  Genetics of epilepsy 
Neurology  2014;83(12):1042-1048.
Objective:
Analysis of twins with epilepsy to explore the genetic architecture of specific epilepsies, to evaluate the applicability of the 2010 International League Against Epilepsy (ILAE) organization of epilepsy syndromes, and to integrate molecular genetics with phenotypic analyses.
Methods:
A total of 558 twin pairs suspected to have epilepsy were ascertained from twin registries (69%) or referral (31%). Casewise concordance estimates were calculated for epilepsy syndromes. Epilepsies were then grouped according to the 2010 ILAE organizational scheme. Molecular genetic information was utilized where applicable.
Results:
Of 558 twin pairs, 418 had confirmed seizures. A total of 534 twin individuals were affected. There were higher twin concordance estimates for monozygotic (MZ) than for dizygotic (DZ) twins for idiopathic generalized epilepsies (MZ = 0.77; DZ = 0.35), genetic epilepsy with febrile seizures plus (MZ = 0.85; DZ = 0.25), and focal epilepsies (MZ = 0.40; DZ = 0.03). Utilizing the 2010 ILAE scheme, the twin data clearly demonstrated genetic influences in the syndromes designated as genetic. Of the 384 tested twin individuals, 10.9% had mutations of large effect in known epilepsy genes or carried validated susceptibility alleles.
Conclusions:
Twin studies confirm clear genetic influences for specific epilepsies. Analysis of the twin sample using the 2010 ILAE scheme strongly supported the validity of grouping the “genetic” syndromes together and shows this organizational scheme to be a more flexible and biologically meaningful system than previous classifications. Successful selected molecular testing applied to this cohort is the prelude to future large-scale next-generation sequencing of epilepsy research cohorts. Insights into genetic architecture provided by twin studies provide essential data for optimizing such approaches.
doi:10.1212/WNL.0000000000000790
PMCID: PMC4166361  PMID: 25107880
17.  A comprehensive evaluation of interaction between genetic variants and use of menopausal hormone therapy on mammographic density 
Introduction
Mammographic density is an established breast cancer risk factor with a strong genetic component and can be increased in women using menopausal hormone therapy (MHT). Here, we aimed to identify genetic variants that may modify the association between MHT use and mammographic density.
Methods
The study comprised 6,298 postmenopausal women from the Mayo Mammography Health Study and nine studies included in the Breast Cancer Association Consortium. We selected for evaluation 1327 single nucleotide polymorphisms (SNPs) showing the lowest P-values for interaction (Pint) in a meta-analysis of genome-wide gene-environment interaction studies with MHT use on risk of breast cancer, 2541 SNPs in candidate genes (AKR1C4, CYP1A1-CYP1A2, CYP1B1, ESR2, PPARG, PRL, SULT1A1-SULT1A2 and TNF) and ten SNPs (AREG-rs10034692, PRDM6-rs186749, ESR1-rs12665607, ZNF365-rs10995190, 8p11.23-rs7816345, LSP1-rs3817198, IGF1-rs703556, 12q24-rs1265507, TMEM184B-rs7289126, and SGSM3-rs17001868) associated with mammographic density in genome-wide studies. We used multiple linear regression models adjusted for potential confounders to evaluate interactions between SNPs and current use of MHT on mammographic density.
Results
No significant interactions were identified after adjustment for multiple testing. The strongest SNP-MHT interaction (unadjusted Pint <0.0004) was observed with rs9358531 6.5kb 5′ of PRL. Furthermore, three SNPs in PLCG2 that had previously been shown to modify the association of MHT use with breast cancer risk were found to modify also the association of MHT use with mammographic density (unadjusted Pint <0.002), but solely among cases (unadjusted Pint SNP×MHT×case-status <0.02).
Conclusions
The study identified potential interactions on mammographic density between current use of MHT and SNPs near PRL and in PLCG2, which require confirmation. Given the moderate size of the interactions observed, larger studies are needed to identify genetic modifiers of the association of MHT use with mammographic density.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0625-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-015-0625-9
PMCID: PMC4537547  PMID: 26275715
18.  Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk 
Chornokur, Ganna | Lin, Hui-Yi | Tyrer, Jonathan P. | Lawrenson, Kate | Dennis, Joe | Amankwah, Ernest K. | Qu, Xiaotao | Tsai, Ya-Yu | Jim, Heather S. L. | Chen, Zhihua | Chen, Ann Y. | Permuth-Wey, Jennifer | Aben, Katja KH. | Anton-Culver, Hoda | Antonenkova, Natalia | Bruinsma, Fiona | Bandera, Elisa V. | Bean, Yukie T. | Beckmann, Matthias W. | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bunker, Clareann H. | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chang-Claude, Jenny | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | du Bois, Andreas | Despierre, Evelyn | Dicks, Ed | Doherty, Jennifer A. | Dörk, Thilo | Dürst, Matthias | Easton, Douglas F. | Eccles, Diana M. | Edwards, Robert P. | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goodman, Marc T. | Gronwald, Jacek | Harrington, Patricia | Harter, Philipp | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A. T. | Hillemanns, Peter | Hogdall, Claus K. | Hogdall, Estrid | Hosono, Satoyo | Jakubowska, Anna | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y. | Kelemen, Linda E. | Kellar, Mellissa | Kiemeney, Lambertus A. | Krakstad, Camilla | Kjaer, Susanne K. | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lim, Boon Kiong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F. A. G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | McNeish, Iain | Menon, Usha | Milne, Roger L. | Modugno, Francesmary | Moysich, Kirsten B. | Ness, Roberta B. | Nevanlinna, Heli | Eilber, Ursula | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Weber, Rachel Palmieri | Paul, James | Pearce, Celeste L. | Pejovic, Tanja | Pelttari, Liisa M. | Pike, Malcolm C. | Poole, Elizabeth M. | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schernhammer, Eva | Schwaab, Ira | Shu, Xiao-Ou | Shvetsov, Yurii B. | Siddiqui, Nadeem | Sieh, Weiva | Song, Honglin | Southey, Melissa C. | Spiewankiewicz, Beata | Sucheston, Lara | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J. | Thomsen, Lotte | Tangen, Ingvild L. | Tworoger, Shelley S. | van Altena, Anne M. | Vierkant, Robert A. | Vergote, Ignace | Walsh, Christine S. | Wang-Gohrke, Shan | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Wu, Anna H. | Wu, Xifeng | Woo, Yin-Ling | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Hasmad, Hanis N. | Berchuck, Andrew | Iversen, Edwin S. | Schildkraut, Joellen M. | Ramus, Susan J. | Goode, Ellen L. | Monteiro, Alvaro N. A. | Gayther, Simon A. | Narod, Steven A. | Pharoah, Paul D. P. | Sellers, Thomas A. | Phelan, Catherine M.
PLoS ONE  2015;10(6):e0128106.
Background
Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.
Methods
In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.
Results
The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4).
Conclusion
These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.
doi:10.1371/journal.pone.0128106
PMCID: PMC4474865  PMID: 26091520
19.  Risk factors for uncommon histologic subtypes of breast cancer using centralized pathology review in the Breast Cancer Family Registry 
Breast cancer research and treatment  2012;134(3):1209-1220.
Epidemiologic studies of histologic types of breast cancer including mucinous, medullary, and tubular carcinomas have primarily relied on International Classification of Diseases-Oncology (ICD-O) codes assigned by local pathologists to define histology. Using data from the Breast Cancer Family Registry (BCFR), we compared histologic agreement between centralized BCFR pathology review and ICD-O codes available from local tumor registries among 3,260 breast cancer cases. Agreement was low to moderate for less common histologies; for example, only 55 and 26 % of cases classified as mucinous and medullary, respectively, by centralized review were similarly classified using ICD-O coding. We then evaluated risk factors for each histologic subtype by comparing each histologic case group defined by centralized review with a common set of 2,997 population-based controls using polytomous logistic regression. Parity [odds ratio (OR) = 0.4, 95 % confidence interval (95 % CI): 0.2–0.9, for parous vs. nulliparous], age at menarche (OR = 0.5, 95 % CI: 0.3–0.9, for age ≥13 vs. ≤11), and use of oral contraceptives (OCs) (OR = 0.5, 95 % CI: 0.2–0.8, OC use >5 years vs. never) were associated with mucinous carcinoma (N = 92 cases). Body mass index (BMI) (OR = 1.05, 95 % CI: 1.0–1.1, per unit of BMI) and high parity (OR = 2.6, 95 % CI: 1.1–6.0 for ≥3 live births vs. nulliparous) were associated with medullary carcinoma (N = 90 cases). We did not find any associations between breast cancer risk factors and tubular carcinoma (N = 86 cases). Relative risk estimates from analyses using ICD-O classifications of histology, rather than centralized review, resulted in attenuated, and/or more imprecise, associations. These findings suggest risk factor heterogeneity across breast cancer tumor histologies, and demonstrate the value of centralized pathology review for classifying rarer tumor types.
doi:10.1007/s10549-012-2056-y
PMCID: PMC4470278  PMID: 22527103
Epidemiology; Mucinous breast cancer; Medullary breast cancer; Centralized pathology; Parity; Oral contraceptives
20.  Crowdsourcing the General Public for Large Scale Molecular Pathology Studies in Cancer 
EBioMedicine  2015;2(7):681-689.
Background
Citizen science, scientific research conducted by non-specialists, has the potential to facilitate biomedical research using available large-scale data, however validating the results is challenging. The Cell Slider is a citizen science project that intends to share images from tumors with the general public, enabling them to score tumor markers independently through an internet-based interface.
Methods
From October 2012 to June 2014, 98,293 Citizen Scientists accessed the Cell Slider web page and scored 180,172 sub-images derived from images of 12,326 tissue microarray cores labeled for estrogen receptor (ER). We evaluated the accuracy of Citizen Scientist's ER classification, and the association between ER status and prognosis by comparing their test performance against trained pathologists.
Findings
The area under ROC curve was 0.95 (95% CI 0.94 to 0.96) for cancer cell identification and 0.97 (95% CI 0.96 to 0.97) for ER status. ER positive tumors scored by Citizen Scientists were associated with survival in a similar way to that scored by trained pathologists. Survival probability at 15 years were 0.78 (95% CI 0.76 to 0.80) for ER-positive and 0.72 (95% CI 0.68 to 0.77) for ER-negative tumors based on Citizen Scientists classification. Based on pathologist classification, survival probability was 0.79 (95% CI 0.77 to 0.81) for ER-positive and 0.71 (95% CI 0.67 to 0.74) for ER-negative tumors. The hazard ratio for death was 0.26 (95% CI 0.18 to 0.37) at diagnosis and became greater than one after 6.5 years of follow-up for ER scored by Citizen Scientists, and 0.24 (95% CI 0.18 to 0.33) at diagnosis increasing thereafter to one after 6.7 (95% CI 4.1 to 10.9) years of follow-up for ER scored by pathologists.
Interpretation
Crowdsourcing of the general public to classify cancer pathology data for research is viable, engages the public and provides accurate ER data. Crowdsourced classification of research data may offer a valid solution to problems of throughput requiring human input.
Highlights
•Crowdsourcing of the general public to classify estrogen receptor in breast tumors was evaluated.•More than 95 thousand volunteers participated of the project over two years.•Citizen Scientists were able to classify estrogen receptors with high accuracy.•The estrogen receptor score assigned by Citizens Scientists was associated with breast cancer patient survival.
doi:10.1016/j.ebiom.2015.05.009
PMCID: PMC4534635  PMID: 26288840
Citizen science; Crowd science; Crowdsourcing; Breast cancer
21.  Common germline polymorphisms associated with breast cancer-specific survival 
Pirie, Ailith | Guo, Qi | Kraft, Peter | Canisius, Sander | Eccles, Diana M | Rahman, Nazneen | Nevanlinna, Heli | Chen, Constance | Khan, Sofia | Tyrer, Jonathan | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | Michailidou, Kyriaki | Lush, Michael | Dunning, Alison M | Shah, Mitul | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Lambrechts, Dieter | Weltens, Caroline | Leunen, Karin | van Ongeval, Chantal | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Blomqvist, Carl | Aittomäki, Kristiina | Fagerholm, Rainer | Muranen, Taru A | Olsen, Janet E | Hallberg, Emily | Vachon, Celine | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Broeks, Annegien | Cornelissen, Sten | Haiman, Christopher A | Henderson, Brian E | Schumacher, Frederick | Le Marchand, Loic | Hopper, John L | Tsimiklis, Helen | Apicella, Carmel | Southey, Melissa C | Cross, Simon S | Reed, Malcolm WR | Giles, Graham G | Milne, Roger L | McLean, Catriona | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Hooning, Maartje J | Hollestelle, Antoinette | Martens, John WM | van den Ouweland, Ans MW | Marme, Federick | Schneeweiss, Andreas | Yang, Rongxi | Burwinkel, Barbara | Figueroa, Jonine | Chanock, Stephen J | Lissowska, Jolanta | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Brenner, Hermann | Butterbach, Katja | Holleczek, Bernd | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Li, Jingmei | Brand, Judith S | Humphreys, Keith | Devilee, Peter | Tollenaar, Robert AEM | Seynaeve, Caroline | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Ficarazzi, Filomena | Beckmann, Matthias W | Hein, Alexander | Ekici, Arif B | Balleine, Rosemary | Phillips, Kelly-Anne | Benitez, Javier | Zamora, M Pilar | Perez, Jose Ignacio Arias | Menéndez, Primitiva | Jakubowska, Anna | Lubinski, Jan | Gronwald, Jacek | Durda, Katarzyna | Hamann, Ute | Kabisch, Maria | Ulmer, Hans Ulrich | Rüdiger, Thomas | Margolin, Sara | Kristensen, Vessela | Nord, Siljie | Evans, D Gareth | Abraham, Jean | Earl, Helena | Poole, Christopher J | Hiller, Louise | Dunn, Janet A | Bowden, Sarah | Yang, Rose | Campa, Daniele | Diver, W Ryan | Gapstur, Susan M | Gaudet, Mia M | Hankinson, Susan | Hoover, Robert N | Hüsing, Anika | Kaaks, Rudolf | Machiela, Mitchell J | Willett, Walter | Barrdahl, Myrto | Canzian, Federico | Chin, Suet-Feung | Caldas, Carlos | Hunter, David J | Lindstrom, Sara | Garcia-Closas, Montserrat | Couch, Fergus J | Chenevix-Trench, Georgia | Mannermaa, Arto | Andrulis, Irene L | Hall, Per | Chang-Claude, Jenny | Easton, Douglas F | Bojesen, Stig E | Cox, Angela | Fasching, Peter A | Pharoah, Paul DP | Schmidt, Marjanka K
Introduction
Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium.
Methods
A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect.
Results
Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease.
Conclusions
Although no variants reached genome-wide significance (P <5 x 10−8), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0570-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-015-0570-7
PMCID: PMC4484708  PMID: 25897948
22.  Identification of Novel Genetic Markers of Breast Cancer Survival 
Guo, Qi | Schmidt, Marjanka K. | Kraft, Peter | Canisius, Sander | Chen, Constance | Khan, Sofia | Tyrer, Jonathan | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Michailidou, Kyriaki | Lush, Michael | Kar, Siddhartha | Beesley, Jonathan | Dunning, Alison M. | Shah, Mitul | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Lambrechts, Diether | Weltens, Caroline | Leunen, Karin | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Blomqvist, Carl | Aittomäki, Kristiina | Fagerholm, Rainer | Muranen, Taru A. | Couch, Fergus J. | Olson, Janet E. | Vachon, Celine | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Broeks, Annegien | Hogervorst, Frans B. | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Hopper, John L. | Tsimiklis, Helen | Apicella, Carmel | Southey, Melissa C. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Giles, Graham G. | Milne, Roger L. | McLean, Catriona | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Hooning, Maartje J. | Hollestelle, Antoinette | Martens, John W. M. | van den Ouweland, Ans M. W. | Marme, Federik | Schneeweiss, Andreas | Yang, Rongxi | Burwinkel, Barbara | Figueroa, Jonine | Chanock, Stephen J. | Lissowska, Jolanta | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Holleczek, Bernd | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Li, Jingmei | Brand, Judith S. | Humphreys, Keith | Devilee, Peter | Tollenaar, Rob A. E. M. | Seynaeve, Caroline | Radice, Paolo | Peterlongo, Paolo | Bonanni, Bernardo | Mariani, Paolo | Fasching, Peter A. | Beckmann, Matthias W. | Hein, Alexander | Ekici, Arif B. | Chenevix-Trench, Georgia | Balleine, Rosemary | Phillips, Kelly-Anne | Benitez, Javier | Zamora, M. Pilar | Arias Perez, Jose Ignacio | Menéndez, Primitiva | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Hamann, Ute | Kabisch, Maria | Ulmer, Hans Ulrich | Rüdiger, Thomas | Margolin, Sara | Kristensen, Vessela | Nord, Silje | Evans, D. Gareth | Abraham, Jean E. | Earl, Helena M. | Hiller, Louise | Dunn, Janet A. | Bowden, Sarah | Berg, Christine | Campa, Daniele | Diver, W. Ryan | Gapstur, Susan M. | Gaudet, Mia M. | Hankinson, Susan E. | Hoover, Robert N. | Hüsing, Anika | Kaaks, Rudolf | Machiela, Mitchell J. | Willett, Walter | Barrdahl, Myrto | Canzian, Federico | Chin, Suet-Feung | Caldas, Carlos | Hunter, David J. | Lindstrom, Sara | García-Closas, Montserrat | Hall, Per | Easton, Douglas F. | Eccles, Diana M. | Rahman, Nazneen | Nevanlinna, Heli | Pharoah, Paul D. P.
Background:
Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer–specific survival.
Methods:
We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)–negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided.
Results:
We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10–8). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust.
Conclusions:
This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.
doi:10.1093/jnci/djv081
PMCID: PMC4555642  PMID: 25890600
23.  Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche 
Perry, John RB | Day, Felix | Elks, Cathy E | Sulem, Patrick | Thompson, Deborah J | Ferreira, Teresa | He, Chunyan | Chasman, Daniel I | Esko, Tõnu | Thorleifsson, Gudmar | Albrecht, Eva | Ang, Wei Q | Corre, Tanguy | Cousminer, Diana L | Feenstra, Bjarke | Franceschini, Nora | Ganna, Andrea | Johnson, Andrew D | Kjellqvist, Sanela | Lunetta, Kathryn L | McMahon, George | Nolte, Ilja M | Paternoster, Lavinia | Porcu, Eleonora | Smith, Albert V | Stolk, Lisette | Teumer, Alexander | Tšernikova, Natalia | Tikkanen, Emmi | Ulivi, Sheila | Wagner, Erin K | Amin, Najaf | Bierut, Laura J | Byrne, Enda M | Hottenga, Jouke-Jan | Koller, Daniel L | Mangino, Massimo | Pers, Tune H | Yerges-Armstrong, Laura M | Zhao, Jing Hua | Andrulis, Irene L | Anton-Culver, Hoda | Atsma, Femke | Bandinelli, Stefania | Beckmann, Matthias W | Benitez, Javier | Blomqvist, Carl | Bojesen, Stig E | Bolla, Manjeet K | Bonanni, Bernardo | Brauch, Hiltrud | Brenner, Hermann | Buring, Julie E | Chang-Claude, Jenny | Chanock, Stephen | Chen, Jinhui | Chenevix-Trench, Georgia | Collée, J. Margriet | Couch, Fergus J | Couper, David | Coveillo, Andrea D | Cox, Angela | Czene, Kamila | D’adamo, Adamo Pio | Smith, George Davey | De Vivo, Immaculata | Demerath, Ellen W | Dennis, Joe | Devilee, Peter | Dieffenbach, Aida K | Dunning, Alison M | Eiriksdottir, Gudny | Eriksson, Johan G | Fasching, Peter A | Ferrucci, Luigi | Flesch-Janys, Dieter | Flyger, Henrik | Foroud, Tatiana | Franke, Lude | Garcia, Melissa E | García-Closas, Montserrat | Geller, Frank | de Geus, Eco EJ | Giles, Graham G | Gudbjartsson, Daniel F | Gudnason, Vilmundur | Guénel, Pascal | Guo, Suiqun | Hall, Per | Hamann, Ute | Haring, Robin | Hartman, Catharina A | Heath, Andrew C | Hofman, Albert | Hooning, Maartje J | Hopper, John L | Hu, Frank B | Hunter, David J | Karasik, David | Kiel, Douglas P | Knight, Julia A | Kosma, Veli-Matti | Kutalik, Zoltan | Lai, Sandra | Lambrechts, Diether | Lindblom, Annika | Mägi, Reedik | Magnusson, Patrik K | Mannermaa, Arto | Martin, Nicholas G | Masson, Gisli | McArdle, Patrick F | McArdle, Wendy L | Melbye, Mads | Michailidou, Kyriaki | Mihailov, Evelin | Milani, Lili | Milne, Roger L | Nevanlinna, Heli | Neven, Patrick | Nohr, Ellen A | Oldehinkel, Albertine J | Oostra, Ben A | Palotie, Aarno | Peacock, Munro | Pedersen, Nancy L | Peterlongo, Paolo | Peto, Julian | Pharoah, Paul DP | Postma, Dirkje S | Pouta, Anneli | Pylkäs, Katri | Radice, Paolo | Ring, Susan | Rivadeneira, Fernando | Robino, Antonietta | Rose, Lynda M | Rudolph, Anja | Salomaa, Veikko | Sanna, Serena | Schlessinger, David | Schmidt, Marjanka K | Southey, Mellissa C | Sovio, Ulla | Stampfer, Meir J | Stöckl, Doris | Storniolo, Anna M | Timpson, Nicholas J | Tyrer, Jonathan | Visser, Jenny A | Vollenweider, Peter | Völzke, Henry | Waeber, Gerard | Waldenberger, Melanie | Wallaschofski, Henri | Wang, Qin | Willemsen, Gonneke | Winqvist, Robert | Wolffenbuttel, Bruce HR | Wright, Margaret J | Boomsma, Dorret I | Econs, Michael J | Khaw, Kay-Tee | Loos, Ruth JF | McCarthy, Mark I | Montgomery, Grant W | Rice, John P | Streeten, Elizabeth A | Thorsteinsdottir, Unnur | van Duijn, Cornelia M | Alizadeh, Behrooz Z | Bergmann, Sven | Boerwinkle, Eric | Boyd, Heather A | Crisponi, Laura | Gasparini, Paolo | Gieger, Christian | Harris, Tamara B | Ingelsson, Erik | Järvelin, Marjo-Riitta | Kraft, Peter | Lawlor, Debbie | Metspalu, Andres | Pennell, Craig E | Ridker, Paul M | Snieder, Harold | Sørensen, Thorkild IA | Spector, Tim D | Strachan, David P | Uitterlinden, André G | Wareham, Nicholas J | Widen, Elisabeth | Zygmunt, Marek | Murray, Anna | Easton, Douglas F | Stefansson, Kari | Murabito, Joanne M | Ong, Ken K
Nature  2014;514(7520):92-97.
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P<5×10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1/WDR25, MKRN3/MAGEL2 and KCNK9) demonstrating parent-of-origin specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signaling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
doi:10.1038/nature13545
PMCID: PMC4185210  PMID: 25231870
24.  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
25.  A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46 450 cases and 42 461 controls from the breast cancer association consortium 
Milne, Roger L. | Herranz, Jesús | Michailidou, Kyriaki | Dennis, Joe | Tyrer, Jonathan P. | Zamora, M. Pilar | Arias-Perez, José Ignacio | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Wang, Qin | Bolla, Manjeet K. | Czene, Kamila | Eriksson, Mikael | Humphreys, Keith | Darabi, Hatef | Li, Jingmei | Anton-Culver, Hoda | Neuhausen, Susan L. | Ziogas, Argyrios | Clarke, Christina A. | Hopper, John L. | Dite, Gillian S. | Apicella, Carmel | Southey, Melissa C. | Chenevix-Trench, Georgia | Swerdlow, Anthony | Ashworth, Alan | Orr, Nicholas | Schoemaker, Minouk | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Wang, Xianshu | Olson, Janet E. | Vachon, Celine | Purrington, Kristen | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Dunning, Alison M. | Shah, Mitul | Guénel, Pascal | Truong, Thérèse | Sanchez, Marie | Mulot, Claire | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J. | Hollestelle, Antoinette | Collée, J. Margriet | Jager, Agnes | Cox, Angela | Brock, Ian W. | Reed, Malcolm W.R. | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Dumont, Martine | Soucy, Penny | Dörk, Thilo | Bogdanova, Natalia V. | Hamann, Ute | Försti, Asta | Rüdiger, Thomas | Ulmer, Hans-Ulrich | Fasching, Peter A. | Häberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Peto, Julian | Radice, Paolo | Peterlongo, Paolo | Peissel, Bernard | Mariani, Paolo | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Marme, Federik | Burwinkel, Barbara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Lambrechts, Diether | Yesilyurt, Betul T. | Floris, Giuseppe | Leunen, Karin | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børresen-Dale, Anne-Lise | García-Closas, Montserrat | Chanock, Stephen J. | Lissowska, Jolanta | Figueroa, Jonine D. | Schmidt, Marjanka K. | Broeks, Annegien | Verhoef, Senno | Rutgers, Emiel J. | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Couch, Fergus J. | Toland, Amanda E. | Yannoukakos, Drakoulis | Pharoah, Paul D.P. | Hall, Per | Benítez, Javier | Malats, Núria | Easton, Douglas F.
Human Molecular Genetics  2013;23(7):1934-1946.
Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10−4) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10−8. Results from the second analytic approach were consistent with those from the first (P > 10−10). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.
doi:10.1093/hmg/ddt581
PMCID: PMC3943524  PMID: 24242184

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