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1.  DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers 
Osorio, Ana | Milne, Roger L. | Kuchenbaecker, Karoline | Vaclová, Tereza | Pita, Guillermo | Alonso, Rosario | Peterlongo, Paolo | Blanco, Ignacio | de la Hoya, Miguel | Duran, Mercedes | Díez, Orland | Ramón y Cajal, Teresa | Konstantopoulou, Irene | Martínez-Bouzas, Cristina | Andrés Conejero, Raquel | Soucy, Penny | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | SWE-BRCA,  | Arver, Brita | Rantala, Johanna | Loman, Niklas | Ehrencrona, Hans | Olopade, Olufunmilayo I. | Beattie, Mary S. | Domchek, Susan M. | Nathanson, Katherine | Rebbeck, Timothy R. | Arun, Banu K. | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | John, Esther M. | Whittemore, Alice S. | Daly, Mary B. | Southey, Melissa | Hopper, John | Terry, Mary B. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Steele, Linda | Neuhausen, Susan L. | Ding, Yuan Chun | Hansen, Thomas v. O. | Jønson, Lars | Ejlertsen, Bent | Gerdes, Anne-Marie | Infante, Mar | Herráez, Belén | Moreno, Leticia Thais | Weitzel, Jeffrey N. | Herzog, Josef | Weeman, Kisa | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Scuvera, Giulietta | Bonanni, Bernardo | Mariette, Frederique | Volorio, Sara | Viel, Alessandra | Varesco, Liliana | Papi, Laura | Ottini, Laura | Tibiletti, Maria Grazia | Radice, Paolo | Yannoukakos, Drakoulis | Garber, Judy | Ellis, Steve | Frost, Debra | Platte, Radka | Fineberg, Elena | Evans, Gareth | Lalloo, Fiona | Izatt, Louise | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Cole, Trevor | Eccles, Diana | Cook, Jackie | Hodgson, Shirley | Brewer, Carole | Tischkowitz, Marc | Douglas, Fiona | Porteous, Mary | Side, Lucy | Walker, Lisa | Morrison, Patrick | Donaldson, Alan | Kennedy, John | Foo, Claire | Godwin, Andrew K. | Schmutzler, Rita Katharina | Wappenschmidt, Barbara | Rhiem, Kerstin | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Plendl, Hans Jörg | Niederacher, Dieter | Sutter, Christian | Wang-Gohrke, Shan | Steinemann, Doris | Preisler-Adams, Sabine | Kast, Karin | Varon-Mateeva, Raymonda | Gehrig, Andrea | Stoppa-Lyonnet, Dominique | Sinilnikova, Olga M. | Mazoyer, Sylvie | Damiola, Francesca | Poppe, Bruce | Claes, Kathleen | Piedmonte, Marion | Tucker, Kathy | Backes, Floor | Rodríguez, Gustavo | Brewster, Wendy | Wakeley, Katie | Rutherford, Thomas | Caldés, Trinidad | Nevanlinna, Heli | Aittomäki, Kristiina | Rookus, Matti A. | van Os, Theo A. M. | van der Kolk, Lizet | de Lange, J. L. | Meijers-Heijboer, Hanne E. J. | van der Hout, A. H. | van Asperen, Christi J. | Gómez Garcia, Encarna B. | Hoogerbrugge, Nicoline | Collée, J. Margriet | van Deurzen, Carolien H. M. | van der Luijt, Rob B. | Devilee, Peter | HEBON,  | Olah, Edith | Lázaro, Conxi | Teulé, Alex | Menéndez, Mireia | Jakubowska, Anna | Cybulski, Cezary | Gronwald, Jacek | Lubinski, Jan | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Johannsson, Oskar Th. | Maugard, Christine | Montagna, Marco | Tognazzo, Silvia | Teixeira, Manuel R. | Healey, Sue | Investigators, kConFab | Olswold, Curtis | Guidugli, Lucia | Lindor, Noralane | Slager, Susan | Szabo, Csilla I. | Vijai, Joseph | Robson, Mark | Kauff, Noah | Zhang, Liying | Rau-Murthy, Rohini | Fink-Retter, Anneliese | Singer, Christian F. | Rappaport, Christine | Geschwantler Kaulich, Daphne | Pfeiler, Georg | Tea, Muy-Kheng | Berger, Andreas | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Lejbkowicz, Flavio | Andrulis, Irene | Mulligan, Anna Marie | Glendon, Gord | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Sunde, Lone | Thomassen, Mads | Kruse, Torben A. | Jensen, Uffe Birk | Friedman, Eitan | Laitman, Yael | Shimon, Shani Paluch | Simard, Jacques | Easton, Douglas F. | Offit, Kenneth | Couch, Fergus J. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Benitez, Javier | Horwitz, Marshall S.
PLoS Genetics  2014;10(4):e1004256.
Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03–1.16), p = 2.7×10−3) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03–1.21, p = 4.8×10−3). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
Author Summary
Women harboring a germ-line mutation in the BRCA1 or BRCA2 genes have a high lifetime risk to develop breast and/or ovarian cancer. However, not all carriers develop cancer and high variability exists regarding age of onset of the disease and type of tumor. One of the causes of this variability lies in other genetic factors that modulate the phenotype, the so-called modifier genes. Identification of these genes might have important implications for risk assessment and decision making regarding prevention of the disease. Given that BRCA1 and BRCA2 participate in the repair of DNA double strand breaks, here we have investigated whether variations, Single Nucleotide Polymorphisms (SNPs), in genes participating in other DNA repair pathway may be associated with cancer risk in BRCA carriers. We have selected the Base Excision Repair pathway because BRCA defective cells are extremely sensitive to the inhibition of one of its components, PARP1. Thanks to a large international collaborative effort, we have been able to identify at least two SNPs that are associated with increased cancer risk in BRCA1 and BRCA2 mutation carriers respectively. These findings could have implications not only for risk assessment, but also for treatment of BRCA1/2 mutation carriers with PARP inhibitors.
PMCID: PMC3974638  PMID: 24698998
2.  Interpretation of single and serial measures of HE4 and CA125 in asymptomatic women at high risk for ovarian cancer 
Human epididymis protein 4 (HE4) is approved for clinical use with CA125 to predict epithelial ovarian cancer (EOC) in women with a pelvic mass or in remission after chemotherapy. Previously reported reference ranges for HE4 are inconsistent.
We report positivity thresholds yielding 90%, 95%, 98% and 99% specificity for age-defined populations of healthy women for HE4, CA125 and Risk of Malignancy Algorithm (ROMA), a weighted average of HE4 and CA125. HE4 and CA125 were measured in 1780 samples from 778 healthy women aged >25 years with a documented deleterious mutation, or aged >35 years with a significant family history. Effects on marker levels of a woman’s age, ethnicity and epidemiologic characteristics were estimated, as were the population-specific means, variances and within- and between-woman variances used to generate longitudinal screening algorithms for these markers.
CA125 levels were lower with Black ethnicity (p=0.008). Smoking was associated with higher HE4 (p=0.007) and ROMA (p<0.019). Continuous oral contraceptive use decreased levels of CA125 (p=0.041), and ROMA (p=0.12). CA125 was lower in women age ≥55, and HE4 increased with age (p<0.01), particularly among women age ≥55.
Due to the strong effect of age on HE4, thresholds for HE4 are best defined for women of specific ages. Age-specific population thresholds for HE4 for 95% specificity ranged from 41.4 pmol/L for women age 30 to 82.1 pmol/L for women age 80.
Incorporation of serial marker values from screening history reduces personalized thresholds for CA125 and HE4 but is inappropriate for ROMA.
PMCID: PMC3493821  PMID: 22962406
ovarian cancer; screening; longitudinal algorithm; HE4; CA125; early detection; high-risk
3.  When parents disclose BRCA1/2 test results: Their communication and perceptions of offspring response 
Cancer  2012;118(13):3417-3425.
BRCA1/2 testing is not recommended for children, as risk reduction measures and screening are not generally recommended before 25 years old (YO). Little is known about the prevalence and predictors of parent communication to offspring and how offspring respond to this communication.
Semi-structured interviews were conducted with parents who had BRCA1/2 testing and at least one child <25 YO. Logistic regressions were utilized to evaluate associations with communication. Framework analysis was utilized to analyze open-ended responses.
253 parents completed interviews (61% response rate), reporting on 505 offspring. 29% of parents were BRCA1/2 mutation carriers. 334 (66%) offspring learned of their parent’s test result. Older offspring age (p<=0.01), offspring gender (female, p=0.05), parents’ negative test result (p=0.03) and parents’ education (high-school only, p=0.02) were associated with communication to offspring. The most frequently reported initial offspring responses were neutral (41%) or relief (28%). 13% of offspring were reported to experience concern or distress (11%) in response to parental communication of their test results. Distress was more frequently perceived among offspring learning of their parent’s BRCA1/2 positive or variant of uncertain significance result.
Many parents communicate their BRCA1/2 test results to young offspring. Parents’ perceptions of offspring responses appear to vary by offspring age and parent test result. A better understanding of how young offspring respond to information about hereditary risk for adult cancer could provide opportunities to optimize adaptive psychosocial responses to risk information and performance of health behaviors, in adolescence and throughout an at-risk lifespan.
PMCID: PMC3326182  PMID: 22231763
4.  Identifying putative breast cancer-associated long intergenic non-coding RNA loci by high density SNP array analysis 
Frontiers in Genetics  2012;3:299.
Recent high-throughput transcript discoveries have yielded a growing recognition of long intergenic non-coding RNAs (lincRNAs), a class of arbitrarily defined transcripts (>200 nt) that are primarily produced from the intergenic space. lincRNAs have been increasingly acknowledged for their expressional dynamics and likely functional associations with cancers. However, differential gene dosage of lincRNA genes between cancer genomes is less studied. By using the high-density Human Omni5-Quad BeadChips (Illumina), we investigated genomic copy number aberrations in a set of seven tumor-normal paired primary human mammary epithelial cells (HMECs) established from patients with invasive ductal carcinoma. This Beadchip platform includes a total of 2,435,915 SNP loci dispersed at an average interval of ~700 nt throughout the intergenic region of the human genome. We mapped annotated or putative lincRNA genes to a subset of 332,539 SNP loci, which were included in our analysis for lincRNA-associated copy number variations (CNV). We have identified 122 lincRNAs, which were affected by somatic CNV with overlapped aberrations ranging from 0.14% to 100% in length. lincRNA-associated aberrations were detected predominantly with copy number losses and preferential clustering to the ends of chromosomes. Interestingly, lincRNA genes appear to be less susceptible to CNV in comparison to both protein-coding and intergenic regions (CNV affected segments in percentage: 1.8%, 37.5%, and 60.6%, respectively). In summary, our study established a novel approach utilizing high-resolution SNP array to identify lincRNA candidates, which could functionally link to tumorigenesis, and provide new strategies for the diagnosis and treatment of breast cancer.
PMCID: PMC3528021  PMID: 23267367
long intergenic non-coding RNA (lincRNA); copy number variation (CNV); SNP array; breast cancer
5.  A prospective study of quality of life among women undergoing risk-reducing salpingo-oophorectomy versus gynecologic screening for ovarian cancer 
Gynecologic oncology  2009;112(3):594-600.
The primary objective of the study was to prospectively assess quality of life (QOL) among women at increased risk of ovarian cancer who are undergoing risk-reducing salpingo-oophorectomy (RRSO) or serial screening.
Women at increased risk of ovarian cancer who were undergoing RRSO were recruited into the study. At-risk women undergoing serial screening for early detection of ovarian cancer served as a comparison group. Participants completed measures of QOL, sexual functioning, body image, depressive symptoms, and a symptom checklist at baseline (prior to surgery for women obtaining RRSO), and then at 1-month, 6-months, and 12-months post baseline.
Women who underwent surgery reported poorer physical functioning, more physical role limitations, greater pain, less vitality, poorer social functioning, and greater discomfort and less satisfaction with sexual activities at 1-month assessment compared to baseline. In contrast, women undergoing screening experienced no significant decrements in QOL or sexual functioning at 1-month assessment. Most QOL deficits observed in the surgical group were no longer apparent by 6-month assessment. Women in the surgery group were more likely to report hot flashes and vaginal dryness, but over time, symptoms of vaginal discomfort decreased to a greater extent in women who had RRSO compared to women undergoing screening. No differences in body image or depressive symptoms were observed between the two groups at any time point.
Short-term deficits in physical functioning and other specific domains of QOL were observed following RRSO, but most women recovered baseline functioning by 6- and 12-month assessments. Issues regarding the potential impact of surgery on short-term sexual functioning should be considered and weighed carefully, particularly among younger women.
PMCID: PMC2697574  PMID: 19141360
quality of life; ovarian cancer; prophylactic surgery; screening
6.  Identifying breast cancer risk loci by global differential allele-specific expression (DASE) analysis in mammary epithelial transcriptome 
BMC Genomics  2012;13:570.
The significant mortality associated with breast cancer (BCa) suggests a need to improve current research strategies to identify new genes that predispose women to breast cancer. Differential allele-specific expression (DASE) has been shown to contribute to phenotypic variables in humans and recently to the pathogenesis of cancer. We previously reported that nonsense-mediated mRNA decay (NMD) could lead to DASE of BRCA1/2, which is associated with elevated susceptibility to breast cancer. In addition to truncation mutations, multiple genetic and epigenetic factors can contribute to DASE, and we propose that DASE is a functional index for cis-acting regulatory variants and pathogenic mutations, and that global analysis of DASE in breast cancer precursor tissues can be used to identify novel causative alleles for breast cancer susceptibility.
To test our hypothesis, we employed the Illumina® Omni1-Quad BeadChip in paired genomic DNA (gDNA) and double-stranded cDNA (ds-cDNA) samples prepared from eight BCa patient-derived normal mammary epithelial lines (HMEC). We filtered original array data according to heterozygous genotype calls and calculated DASE values using the Log ratio of cDNA allele intensity, which was normalized to the corresponding gDNA. We developed two statistical methods, SNP- and gene-based approaches, which allowed us to identify a list of 60 candidate DASE loci (DASE ≥ 2.00, P ≤ 0.01, FDR ≤ 0.05) by both methods. Ingenuity Pathway Analysis of DASE loci revealed one major breast cancer-relevant interaction network, which includes two known cancer causative genes, ZNF331 (DASE = 2.31, P = 0.0018, FDR = 0.040) and USP6 (DASE = 4.80, P = 0.0013, FDR = 0.013), and a breast cancer causative gene, DMBT1 (DASE=2.03, P = 0.0017, FDR = 0.014). Sequence analysis of a 5′ RACE product of DMBT1 demonstrated that rs2981745, a putative breast cancer risk locus, appears to be one of the causal variants leading to DASE in DMBT1.
Our study demonstrated for the first time that global DASE analysis is a powerful new approach to identify breast cancer risk allele(s).
PMCID: PMC3532379  PMID: 23107584
Differential allele-specific expression; Breast cancer susceptibility; SNP array; DMBT1
7.  Large Prospective Study of Ovarian Cancer Screening in High-risk Women: CA125 Cut-point Defined by Menopausal Status 
Previous screening trials for early detection of ovarian cancer in postmenopausal women have used the standard CA125 cut-point of 35 U/mL, the 98th percentile in this population yielding a 2% false positive rate, while the same cut-point in trials of premenopausal women results in substantially higher false positive rates. We investigated demographic and clinical factors predicting CA125 distributions, including 98th percentiles, in a large population of high-risk women participating in two ovarian cancer screening studies with common eligibility criteria and screening protocols.
Baseline CA125 values and clinical and demographic data from 3,692 women participating in screening studies conducted by the NCI-sponsored Cancer Genetics Network and Gynecologic Oncology Group were combined for this pre-planned analysis. Due to the large effect of menopausal status on CA125 levels, statistical analyses were conducted separately in pre- and postmenopausal subjects to determine the impact of other baseline factors on predicted CA125 cut-points based on the 98th percentile.
The primary clinical factor affecting CA125 cut-points was menopausal status, with premenopausal women having a significantly higher cut-point of 50 U/mL while in postmenopausal subjects the standard cut-point of 35 U/mL was recapitulated. In premenopausal women, current oral contraceptive (OC) users had a cut-point of 40 U/mL.
To achieve a 2% false positive rate in ovarian cancer screening trials and in high-risk women choosing to be screened, the cut-point for initial CA125 testing should be personalized primarily for menopausal status (~ 50 for premenopausal women, 40 for premenopausal on OC, 35 for postmenopausal women).
PMCID: PMC3172691  PMID: 21893500
CA125; ovarian cancer screening; biomarker
8.  Risk-Reducing Salpingo-Oophorectomy for the Prevention of BRCA1- and BRCA2-Associated Breast and Gynecologic Cancer: A Multicenter, Prospective Study 
Journal of Clinical Oncology  2008;26(8):1331-1337.
Risk-reducing salpingo-oophorectomy (RRSO) has been widely adopted as a key component of breast and gynecologic cancer risk-reduction for women with BRCA1 and BRCA2 mutations. Despite 17% to 39% of all BRCA mutation carriers having a mutation in BRCA2, no prospective study to date has evaluated the efficacy of RRSO for the prevention of breast and BRCA-associated gynecologic (ovarian, fallopian tube or primary peritoneal) cancer when BRCA2 mutation carriers are analyzed separately from BRCA1 mutation carriers.
Patients and Methods
A total of 1,079 women 30 years of age and older with ovaries in situ and a deleterious BRCA1 or BRCA2 mutation were enrolled onto prospective follow-up studies at one of 11 centers from November 1, 1994 to December 1, 2004. Women self-selected RRSO or observation. Follow-up information through November 30, 2005, was collected by questionnaire and medical record review. The effect of RRSO on time to diagnosis of breast or BRCA-associated gynecologic cancer was analyzed using a Cox proportional-hazards model.
During 3-year follow-up, RRSO was associated with an 85% reduction in BRCA1-associated gynecologic cancer risk (hazard ratio [HR] = 0.15; 95% CI, 0.04 to 0.56) and a 72% reduction in BRCA2-associated breast cancer risk (HR = 0.28; 95% CI, 0.08 to 0.92). While protection against BRCA1-associated breast cancer (HR = 0.61; 95% CI, 0.30 to 1.22) and BRCA2-associated gynecologic cancer (HR = 0.00; 95% CI, not estimable) was suggested, neither effect reached statistical significance.
The protection conferred by RRSO against breast and gynecologic cancers may differ between carriers of BRCA1 and BRCA2 mutations. Further studies evaluating the efficacy of risk-reduction strategies in BRCA mutation carriers should stratify by the specific gene mutated.
PMCID: PMC3306809  PMID: 18268356
9.  Delivery of Internet-based cancer genetic counselling services to patients’ homes: a feasibility study 
We examined the feasibility of home videoconferencing for providing cancer genetic education and risk information to people at-risk. Adults with possible hereditary colon or breast-ovarian cancer syndromes were offered Internet-based counselling. Participants were sent webcams and software to install on their home PCs. They watched a pre-recorded educational video and then took part in a live counselling session with a genetic counsellor. 31 participants took part in Internet counselling sessions. Satisfaction with counselling was high in all domains studied, including technical (mean 4.3 on scale from 1–5), education (mean 4.7), communication (mean 4.8), psychosocial (mean 4.1), and overall (mean 4.2). Qualitative data identified technical aspects that could be improved. All participants reported that they would recommend Internet-based counselling to others. Internet-based genetic counselling is feasible and associated with a high level of satisfaction among participants.
PMCID: PMC3263376  PMID: 21097566
10.  New Strategies in Ovarian Cancer: Uptake and experience of women at high risk of ovarian cancer who are considering risk-reducing salpingo-oophorectomy 
This paper reviews factors associated with uptake of risk-reducing salpingo-oophorectomy by women at increased hereditary risk for ovarian cancer, as well as quality of life issues following surgery. Forty one research studies identified through PubMed and PsychInfo met inclusion criteria. Older age, having had children, a family history of ovarian cancer, a personal history of breast cancer, prophylactic mastectomy, and BRCA1/2 mutation carrier status increase the likelihood of undergoing surgery. Psychosocial variables predictive of surgery uptake include greater perceived risk of ovarian cancer and cancer-related anxiety. Most women report satisfaction with their decision to undergo surgery and both lower perceived ovarian cancer risk and less cancer-related anxiety as benefits. Hormonal deprivation is the main disadvantage reported, particularly by premenopausal women who are not on hormonal replacement therapy (HRT). The evidence is mixed regarding satisfaction with the level of information provided prior to surgery, although generally women report receiving insufficient information regarding the pros and cons of HRT. These findings indicate that when designing decision aids, demographic, medical history, and psychosocial variables need to be addressed in order to facilitate quality decision making.
PMCID: PMC3107031  PMID: 20829330
ovarian risk; prophylactic oophorectomy; patient decision making; quality of life
11.  The Identification of Cognitive Profiles among Women Considering BRCA1/2 Testing through the Utilization of Cluster Analytic Techniques 
Psychology & health  2011;26(10):1327-1343.
Based on the Cognitive-Social Health Information Processing model, we identified cognitive profiles of women at risk for breast and ovarian cancer. Prior to genetic counseling, participants (N = 171) completed a study questionnaire concerning their cognitive and affective responses to to being at genetic risk. Using cluster analysis, four cognitive profiles were generated: (a) high perceived risk/low coping; (b) low value of screening/high expectancy of cancer; (c) moderate perceived risk/moderate efficacy of prevention/low informativeness of test result; and (d) high efficacy of prevention/high coping. The majority of women in clusters one, two and three were unaffected, whereas cluster four consisted almost entirely of affected women. Women in cluster one had the highest number of affected relatives and experienced higher levels of distress than women in the other three clusters. These results highlight the need to consider the psychological profile of women undergoing genetic testing when designing counseling interventions and messages.
PMCID: PMC3197930  PMID: 21756124
breast and ovarian cancer risk; cluster analysis; cognitive profiles; genetic testing; psychological distress
12.  Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts 
The CHEK2-1100delC mutation is recurrent in the population and is a moderate risk factor for breast cancer. To identify additional CHEK2 mutations potentially contributing to breast cancer susceptibility, we sequenced 248 cases with early-onset disease; functionally characterized new variants and conducted a population-based case–control analysis to evaluate their contribution to breast cancer risk. We identified 1 additional null mutation and 5 missense variants in the germline of cancer patients. In vitro, the CHEK2-H143Y variant resulted in gross protein destabilization, while others had variable suppression of in vitro kinase activity using BRCA1 as a substrate. The germline CHEK2-1100delC mutation was present among 8/1,646 (0.5%) sporadic, 2/400 (0.5%) early-onset and 3/302 (1%) familial breast cancer cases, but undetectable amongst 2,105 multiethnic controls, including 633 from the US. CHEK2-positive breast cancer families also carried a deleterious BRCA1 mutation. 1100delC appears to be the only recurrent CHEK2 mutation associated with a potentially significant contribution to breast cancer risk in the general population. Another recurrent mutation with attenuated in vitro function, CHEK2-P85L, is not associated with increased breast cancer susceptibility, but exhibits a striking difference in frequency across populations with different ancestral histories. These observations illustrate the importance of genotyping ethnically diverse groups when assessing the impact of low-penetrance susceptibility alleles on population risk. Our findings highlight the notion that clinical testing for rare missense mutations within CHEK2 may have limited value in predicting breast cancer risk, but that testing for the 1100delC variant may be valuable in phenotypically- and geographically-selected populations.
PMCID: PMC3090684  PMID: 17721994
CHEK2; susceptibility; breast; cancer; mutation
13.  Cancer Genetic Risk Assessment and Referral Patterns in Primary Care 
Purpose: This study was undertaken to describe cancer risk assessment practices among primary care providers (PCPs). Methods: An electronic survey was sent to PCPs affiliated with a single insurance carrier. Demographic and practice characteristics associated with cancer genetic risk assessment and testing activities were described. Latent class analysis supported by likelihood ratio tests was used to define PCP profiles with respect to the level of engagement in genetic risk assessment and referral activity based on demographic and practice characteristics. Results: 860 physicians responded to the survey (39% family practice, 29% internal medicine, 22% obstetrics/gynecology (OB/GYN), 10% other). Most respondents (83%) reported that they routinely assess hereditary cancer risk; however, only 33% reported that they take a full, three-generation pedigree for risk assessment. OB/GYN specialty, female gender, and physician access to a genetic counselor were independent predictors of referral to cancer genetics specialists. Three profiles of PCPs, based upon referral practice and extent of involvement in genetics evaluation, were defined. Conclusion: Profiles of physician characteristics associated with varying levels of engagement with cancer genetic risk assessment and testing can be identified. These profiles may ultimately be useful in targeting decision support tools and services.
PMCID: PMC2935840  PMID: 20001580
14.  A risk variant in a miR-125b binding site in BMPR1B is associated with breast cancer pathogenesis 
Cancer research  2009;69(18):7459-7465.
MicroRNAs regulate diverse cellular processes and play an integral role in cancer pathogenesis. Genomic variation within miRNA target sites may therefore be important sources for genetic differences in cancer risk. To investigate this possibility, we mapped HapMap SNPs to putative miRNA recognition sites within genes dysregulated in estrogen receptor stratified breast tumors and used local linkage disequilibirum (LD) patterns to identify high-ranking SNPs in the Cancer Genetic Markers of Susceptibility (CGEMS) breast cancer genome wide association study (GWAS) for further testing. Two SNPs, rs1970801 and rs11097457, scoring in the top 100 from the CGEMS study, were in strong LD with rs1434536 – a SNP that resides within a miR-125b target site in the 3'UTR of the Bone Morphogenic Receptor Type 1B (BMPR1B) gene encoding a transmembrane serine/threonine kinase. We validated the CGEMS association findings for rs1970801 in an independent cohort of admixture corrected cases identified from families with multiple case histories. Subsequent association testing of rs1434536 for these cases and CGEMS controls with imputed genotypes supported the association. Furthermore, luciferase reporter assays and overexpression of miR-125b-mimics combined with quantitative RT-PCR showed that BMPR1B transcript is a direct target of miR-125b and that miR-125b differentially regulates the C and T alleles of rs1434536. These results suggest that allele-specific regulation of BMPR1B by miR-125b explains the observed disease risk. Our approach is general and can help identify and explain the mechanisms behind disease-association for alleles that affect miRNA regulation.
PMCID: PMC2747041  PMID: 19738052
microRNA; breast cancer; single nucleotide polymorphism; data integration; GWAS
15.  The Impact of Social Roles on the Experience of Men in BRCA1/2 Families: Implications for Counseling 
Journal of genetic counseling  2008;18(1):42-48.
Recent advances in genetics have identified several genes associated with inherited susceptibility to breast and ovarian cancer and have led to the commercial availability of mutation analyses. Although the majority of cancers associated with BRCA1/2 mutations are seen in women, men with BRCA1/2 mutations are at increased risk for male breast cancer, prostate cancer, pancreatic cancer and melanoma. Limited data available on the response of men in BRCA1/2 families suggest that the majority do not pursue genetic counseling, thus they may forgo the opportunity to improve health practices and to pass on valuable cancer risk information to offspring. The patterns of relationships of men within the family and society can pose challenges to their recognition of genetic health threats and the need for preventive interventions. Genetic counselors are in a position to inform at-risk males of their genetic risk, and to help them explore their personal health options.
PMCID: PMC2629810  PMID: 18688698
Hereditary cancer; BRCA1/2 mutations; genetic counseling; male family members
16.  Knowledge and perceptions of familial and genetic risks for breast cancer risk in adolescent girls 
Evidence suggests early events might modify adult breast cancer risk and many adolescents learn of familial and genetic risks for breast cancer. Little is known about how adolescent girls understand and respond to breast cancer risk.
Semi-structured interviews with 11-19 year-old girls at high-risk and population-risk for breast cancer evaluated knowledge and perceptions of breast cancer risk and risk modification. Framework analysis and descriptive statistics were utilized to analyze open-ended responses. Risk group and age differences were evaluated by Fisher’s exact and McNemar’s tests.
54 girls (86% of invited), 35 high-risk (65%) and 19 population-risk (35%) completed interviews. The most frequently reported risk for breast cancer was family history/hereditary predisposition (66%). Only 17% of girls were aware of BRCA1/2 genes. The majority (76%) of high-risk girls perceive themselves to be at increased risk for breast cancer, compared to 22% of population-risk girls (p=0.001). Half of girls reported that women can get breast cancer before 20 years old. The majority believe there are things women (70%) and girls (67%) can do to prevent breast cancer. Mother was the most frequently reported source of information for breast cancer among both high-risk (97%) and population-risk (89%) girls.
In this study, many high-risk girls perceive themselves to be at increased risk for breast cancer, and many girls believe that breast cancer can occur in teens. Yet, most girls believe there are things women and girls can do to prevent breast cancer. Research evaluating the impact of awareness and perceptions of breast cancer risk on psychosocial, health and risk behaviors is needed to develop strategies to optimize responses to cancer risk.
PMCID: PMC3513641  PMID: 23065030
Adolescents; Breast cancer; Breast cancer prevention; Cancer Risk Assessment; Perceived risk of cancer
17.  Measuring, and identifying predictors of, women’s perceptions of three types of breast cancer risk: population risk, absolute risk and comparative risk 
British journal of cancer  2009;100(4):583-589.
A key function of cancer genetics services is to provide risk information. Yet, to date there has been little consistency in the way that breast cancer risk perception has been measured. The aims of the study were to measure estimates of (i) population risk (ii) absolute risk (iii) comparative risk of developing breast cancer for Ashkenazi Jewish women, and to determine predictors of breast cancer risk perception. Of 152 women, 107 (70%) completed all questions. The mean (s.d.) estimate for population risk, absolute risk and comparative risk were 22.7% (15.9), 31.8% (20.6) and 1.9-fold (1.9), respectively. Most women over-estimated population risk. Women at population risk generally over-estimated the population risk and their own absolute risk, yet understood they are at the same risk as the population. Those with a family history understood they are at increased risk, but underestimated the extent to which their familial risk is increased. Anxiety, high estimation of population risk and lesser family history predicted over-estimation of absolute risk, while high estimation of population risk and a strong family history predicted under-estimation of comparative risk.
PMCID: PMC2653735  PMID: 19209174
Ashkenazi; breast cancer; perceived risk; genetic counselling; BRCA1; BRCA2
18.  Dietary intake and breast density in high-risk women: a cross-sectional study 
Women with a family history of breast cancer may be at higher risk for breast cancer, but few previous studies evaluating diet and breast cancer have focused on such women. The objective of the present study was to determine whether diet, a modifiable risk factor, is related to breast density among women at high genetic risk for breast cancer.
Women with at least one first-degree or second-degree relative with breast cancer or ovarian cancer participating in the Fox Chase Cancer Center Family Risk Assessment Program completed health history and food frequency questionnaires and received standard screening mammograms. Cranial–caudal mammographic images were classified into the four Breast Imaging Reporting and Data System categories ranging from 'entirely fatty' to 'extremely dense'. Logistic regression analysis using proportional odds models for polychotomous outcomes provided estimates of odds ratios for having a higher category versus a lower category of breast density.
Among 157 high-risk women, breast density was inversely associated with vitamin D intake (odds ratio for third tertile versus first tertile, 0.5; 95% confidence interval, 0.2–1.0). In contrast, intakes above the median level for protein (odds ratio, 3.0; 95% confidence interval, 1.3–6.9) and above the median level for animal protein (odds ratio, 4.3; 95% confidence interval, 1.8–10.3) were associated with higher breast density, but only among women whose family history did not reflect a known familial cancer syndrome or a breast cancer predisposition gene.
For women with a strong family history that was not associated with known cancer syndromes, dietary factors may be associated with breast density, a strong predictor of breast cancer risk. Since women with strong family history are often very motivated to change their lifestyle habits, further studies are needed to confirm whether changes in diet will change the breast density and the subsequent onset of breast cancer in these women.
PMCID: PMC2242670  PMID: 17949495
19.  Association Between BRCA1 and BRCA2 Mutations and Survival in Women with Invasive Epithelial Ovarian Cancer 
Bolton, Kelly L. | Chenevix-Trench, Georgia | Goh, Cindy | Sadetzki, Siegal | Ramus, Susan J. | Karlan, Beth Y. | Lambrechts, Diether | Despierre, Evelyn | Barrowdale, Daniel | McGuffog, Lesley | Healey, Sue | Easton, Douglas F. | Sinilnikova, Olga | Benitez, Javier | García, María J. | Neuhausen, Susan | Gail, Mitchell H. | Hartge, Patricia | Peock, Susan | Frost, Debra | Evans, D. Gareth | Eeles, Ros | Godwin, Andrew K. | Daly, Mary B. | Kwong, Ava | Ma, Edmond SK | Lázaro, Conxi | Blanco, Ignacio | Montagna, Marco | D’Andrea, Emma | Nicoletto, Ornella | Investigators, kConFab | Johnatty, Sharon E. | Kjær, Susanne Krüger | Jensen, Allan | Høgdall, Estrid | Goode, Ellen L. | Fridley, Brooke L. | Loud, Jennifer T. | Greene, Mark H. | Mai, Phuong L. | Chetrit, Angela | Lubin, Flora | Hirsh-Yechezkel, Galit | Glendon, Gord | Andrulis, Irene L. | Toland, Amanda E. | Senter, Leigha | Gore, Martin E. | Gourley, Charlie | Michie, Caroline O | Song, Honglin | Tyrer, Jonathan | Whittemore, Alice S. | McGuire, Valerie | Sieh, Weiva | Kristoffersson, Ulf | Olsson, Håkan | Borg, Åke | Levine, Douglas A. | Steele, Linda | Beattie, Mary S. | Chan, Salina | Nussbaum, Robert | Moysich, Kirsten B. | Gross, Jenny | Cass, Ilana | Walsh, Christine | Li, Andrew J. | Leuchter, Ronald | Gordon, Ora | Garcia-Closas, Montserrat | Gayther, Simon A. | Chanock, Stephen J. | Antoniou, Antonis C. | Pharoah, Paul D.P.
Approximately 10 percent of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent report suggested that BRCA2 related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear.
To characterize the survival of BRCA carriers with EOC compared to non-carriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns.
Design, Setting, and Participants
We pooled data from 26 studies on the survival of women with ovarian cancer. This included data on 1,213 EOC cases with pathogenic germline mutations in BRCA1 (909) or BRCA2 (304) and 2,666 non-carriers recruited and followed for variable times between 1987 and 2010; the median year of diagnosis was 1998.
Main Outcome Measures
Five year overall mortality.
The five-year overall survival was 36 percent (95% CI: 34–38) for non-carriers, 44 percent (95% CI: 40–48) for BRCA1 carriers and 52 percent (95% CI: 46–58) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 carriers showed a more favorable survival than non-carriers (BRCA1, HR=0.78; 95% CI=0.68–0.89, P=2×10−4; BRCA2, HR = 0.61; 95% CI=0.50–0.76, P=6×10−6). These survival differences remained after additional adjustment for stage, grade, histology and age at diagnosis (BRCA1, HR=0.73, 95% CI=0.64–0.84, P=2×10−5; BRCA2, HR = 0.49, 95% CI=0.39–0.61, P=3×10−10).
Among patients with invasive epithelial ovarian cancer, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival.
PMCID: PMC3727895  PMID: 22274685
20.  Breast and Ovarian Cancer Risk and Risk Reduction in Jewish BRCA1/2 Mutation Carriers 
Journal of Clinical Oncology  2012;30(12):1321-1328.
Mutations in BRCA1/2 dramatically increase the risk of both breast and ovarian cancers. Three mutations in these genes (185delAG, 5382insC, and 6174delT) occur at high frequency in Ashkenazi Jews. We evaluated how these common Jewish mutations (CJMs) affect cancer risks and risk reduction.
Our cohort comprised 4,649 women with disease-associated BRCA1/2 mutations from 22 centers in the Prevention and Observation of Surgical End Points Consortium. Of these women, 969 were self-identified Jewish women. Cox proportional hazards models were used to estimate breast and ovarian cancer risks, as well as risk reduction from risk-reducing salpingo-oophorectomy (RRSO), by CJM and self-identified Jewish status.
Ninety-one percent of Jewish BRCA1/2-positive women carried a CJM. Jewish women were significantly more likely to undergo RRSO than non-Jewish women (54% v 41%, respectively; odds ratio, 1.87; 95% CI, 1.44 to 2.42). Relative risks of cancer varied by CJM, with the relative risk of breast cancer being significantly lower in 6174delT mutation carriers than in non-CJM BRCA2 carriers (hazard ratio, 0.35; 95% CI, 0.18 to 0.69). No significant difference was seen in cancer risk reduction after RRSO among subgroups.
Consistent with previous results, risks for breast and ovarian cancer varied by CJM in BRCA1/2 carriers. In particular, 6174delT carriers had a lower risk of breast cancer. This finding requires additional confirmation in larger prospective and population-based cohort studies before being integrated into clinical care.
PMCID: PMC3341145  PMID: 22430266
21.  Genetic Variation in IGF2 and HTRA1 and Breast Cancer Risk among BRCA1 and BRCA2 Carriers 
BRCA1 and BRCA2 mutation carriers have a lifetime breast cancer risk of 40% to 80%, suggesting the presence of risk modifiers. We previously identified significant associations in genetic variants in the insulin-like growth factor (IGF) signaling pathway. Here, we investigate additional IGF signaling genes as risk modifiers for breast cancer development in BRCA carriers.
A cohort of 1,019 BRCA1 and 500 BRCA2 mutation carriers were genotyped for 99 single-nucleotide polymorphisms (SNP) in 13 genes. Proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was used. For an SNP analysis, no additivity assumptions were made.
Significant associations were found between risk of breast cancer and LD blocks in IGF2 for BRCA1 and BRCA2 mutation carriers (global P values of 0.009 for BRCA1 and 0.007 for BRCA2), HTRA1 for BRCA1 carriers (global P value of 0.005), and MMP3 for BRCA2 carriers (global P = 0.0000007 for BRCA2).
We identified significant associations of genetic variants involved in IGF signaling. With the known interaction of BRCA1 and IGF signaling and the loss of PTEN in a majority of BRCA1 tumors, this suggests that signaling through AKT may modify breast cancer risk in BRCA1 carriers.
These results suggest potential avenues for future research targeting the IGF signaling pathway in modifying risk in BRCA1and BRCA2 mutation carriers.
PMCID: PMC3352680  PMID: 21708937
22.  Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1 Interacting Genes 
Cancer research  2011;71(17):5792-5805.
Inherited BRCA1 mutations confer elevated breast cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, TOPBP1 and time to breast and ovarian cancer diagnosis. False Discovery Rate (FDR) adjusted p-value for overall association of haplotypes (pFDR) with breast cancer were identified at ATM (pFDR =0.029), BRCC45 (pFDR=0.0.19), BRIP1 (pFDR =0.008), CTIP (pFDR =0.017), MERIT40 (pFDR =0.019), NBS1 (pFDR=0.003), RAD50 (pFDR=0.014), and TOPBP1 (pFDR =0.011) and were associated with breast cancer risk. Haplotypes at ABRA1 (pFDR=0.007), BRCC45 (pFDR=0.016 and pFDR=0.005 in two haplotype blocks) and RAP80 (pFDR<0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.
PMCID: PMC3170727  PMID: 21799032
23.  Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1 Interacting Genes 
Cancer research  2011;71(17):5792-5805.
Inherited BRCA1 mutations confer elevated breast cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, TOPBP1 and time to breast and ovarian cancer diagnosis. False Discovery Rate (FDR) adjusted p-value for overall association of haplotypes (pFDR) with breast cancer were identified at ATM (pFDR =0.029), BRCC45 (pFDR=0.0.19), BRIP1 (pFDR =0.008), CTIP (pFDR =0.017), MERIT40 (pFDR =0.019), NBS1 (pFDR=0.003), RAD50 (pFDR=0.014), and TOPBP1 (pFDR =0.011) and were associated with breast cancer risk. Haplotypes at ABRA1 (pFDR=0.007), BRCC45 (pFDR=0.016 and pFDR=0.005 in two haplotype blocks) and RAP80 (pFDR<0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.
PMCID: PMC3170727  PMID: 21799032
24.  Genetic counselor opinions of, and experiences with telephone communication of BRCA1/2 test results 
Clinical genetics  2010;79(2):125-131.
BRCA1/2 test disclosure has, historically, been conducted in-person by genetics professionals. Given increasing demand for, and access to, genetic testing, interest in telephone and Internet genetic services, including disclosure of test results, has increased.
Semi-structured interviews with genetic counselors were conducted to determine interest in, and experiences with telephone disclosure of BRCA1/2 test results. Descriptive data are summarized with response proportions.
194 genetic counselors completed self-administered surveys via the web. Although 98% had provided BRCA1/2 results by telephone, 77% had never provided pre-test counseling by telephone. Genetic counselors reported perceived advantages and disadvantages to telephone disclosure. Thirty-two percent of participants described experiences that made them question this practice. Genetic counselors more frequently reported discomfort with telephone disclosure of a positive result or variant of uncertain significance (p<0.01) than other results. Overall, 73% of participants reported interest in telephone disclosure.
Many genetic counselors have provided telephone disclosure, however, most, infrequently. Genetic counselors identify potential advantages and disadvantages to telephone disclosure, and recognize the potential for testing and patient factors to impact patient outcomes. Further research evaluating the impact of testing and patient factors on cognitive, affective, social and behavioral outcomes of alternative models of communicating genetic information is warranted.
PMCID: PMC3059740  PMID: 21039431
BRCA 1/2; communication; genetic counselors; genetic testing; telephone
25.  Contribution of large genomic BRCA1 alterations to early-onset breast cancer selected for family history and tumour morphology: a report from The Breast Cancer Family Registry 
Selecting women affected with breast cancer who are most likely to carry a germline mutation in BRCA1 and applying the most appropriate test methodology remains challenging for cancer genetics services. We sought to test the value of selecting women for BRCA1 mutation testing on the basis of family history and/or breast tumour morphology criteria as well as the value of testing for large genomic alterations in BRCA1.
We studied women participating in the Breast Cancer Family Registry (BCFR), recruited via population-based sampling, who had been diagnosed with breast cancer before the age of 40 years who had a strong family history of breast or ovarian cancer (n = 187) and/or a first primary breast tumour with morphological features consistent with carrying a BRCA1 germline mutation (n = 133; 37 met both criteria). An additional 184 women diagnosed before the age of 40 years who had a strong family history of breast or ovarian cancer and who were not known to carry a germline BRCA1 mutation were selected from among women who had been recruited into the BCFR from clinical genetics services. These 467 women had been screened for BRCA1 germline mutations, and we expanded this testing to include a screen for large genomic BRCA1 alterations using Multiplex Ligation-dependent Probe Amplification.
Twelve large genomic BRCA1 alterations were identified, including 10 (4%) of the 283 women selected from among the population-based sample. In total, 18 (12%), 18 (19%) and 16 (43%) BRCA1 mutations were identified in the population-based groups selected on the basis of family history only (n = 150), the group selected on the basis of tumour morphology only (n = 96) and meeting both criteria (n = 37), respectively.
Large genomic alterations accounted for 19% of all BRCA1 mutations identified. This study emphasises the value of combining information about family history, age at diagnosis and tumour morphology when selecting women for germline BRCA1 mutation testing as well as including a screen for large genomic alterations.
PMCID: PMC3109582  PMID: 21281505

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