Susan M Domchek

University of Pennsylvania, Filadelfia, Pennsylvania, United States

Are you Susan M Domchek?

Claim your profile

Publications (203)1498.79 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE. The purpose of this article is to assess the difference in fibroglandular volume and background parenchymal enhancement in BRCA1 and BRCA2 mutation carriers on contrast-enhanced breast MRI (CE-MRI) performed before and immediately after risk-reducing salpingo-oophorectomy (RRSO). MATERIALS AND METHODS. We retrospectively compared fibroglandular volume and background parenchymal enhancement in 55 female BRCA1 and BRCA2 mutation carriers before and after RRSO using standard BI-RADS categories and a paired Wilcoxon and Mann-Whitney U test. A two-sample Wilcoxon test was performed to compare fibroglandular volume and background parenchymal enhancement in women with and without subsequent breast cancer diagnosis on follow-up. RESULTS. The median time to post-RRSO CE-MRI was 8 months (range, 1-40 months). There was no difference in fibroglandular volume before and after RRSO (p = 0.65). The mean background parenchymal enhancement was 2.5 (range, 1-4) before and 1.5 (range, 1-4) after RRSO (overall range, -2.5 to 1.5; p = 0.0001). Breast cancer was detected in nine women at a median time of 4.8 years (range, 1.8-13.3 years) after RRSO. For women who received a diagnosis of breast cancer after RRSO compared with those who did not, mean background parenchymal enhancement before RRSO was 3 (range, 2-4) versus 2.5 (range, 1-4; p = 0.001), and mean background parenchymal enhancement after RRSO was 2.5 (range, 1.5-4) versus 1.5 (range 2-4; p = 0.0018). There was no difference in fibroglandular volume before and after RRSO. CONCLUSION. In BRCA1 and BRCA2 mutation carriers, we observed a significant reduction in background parenchymal enhancement on the first CE-MRI after RRSO and no significant change in fibroglandular volume. Higher background parenchymal enhancement before and after RRSO was observed in women who subsequently received a diagnosis of breast cancer. This suggests that background parenchymal enhancement, rather than fibro-glandular volume, may be a more sensitive imaging biomarker of breast cancer risk.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: IntroductionMammography screening results in a significant number of false-positives. The use of pre-test breast cancer risk factors to guide follow-up of abnormal mammograms could improve the positive predictive value of screening. We evaluated the use of the Gail model, body mass index (BMI), and genetic markers to predict cancer diagnosis among women with abnormal mammograms. We also examined the extent to which pre-test risk factors could reclassify women without cancer below the biopsy threshold.Methods We recruited a prospective cohort of women referred to biopsy with abnormal (BI-RADS 4) mammograms. Breast cancer risk factors were assessed prior to biopsy. A validated panel of 12 single nucleotide polymorphisms (SNPs) associated with breast cancer were measured. Logistic regression was used to assess the association of Gail risk factors, BMI and SNPs with cancer diagnosis (invasive or DCIS). Model discrimination was assessed using area under the receiver operating curve and calibration was assessed using the Hosmer-Lemeshow goodness of fit test. Finally, the distribution of predicted probabilities of cancer diagnosis were compared for women with and without breast cancer.ResultsIn the multivariate model, age (OR¿=¿1.05, 95% CI 1.03 to 1.08 P <0.001), SNP panel relative risk (OR¿=¿2.30, 95% CI 1.06 to 4.99, P¿=¿0.035), and BMI (¿30 kg/m2 versus <25 kg/m2, OR¿=¿2.20, 95% CI 1.05 to 4.58, P¿=¿0.036) were significantly associated with breast cancer diagnosis. Older women were more likely to be diagnosed with breast cancer. The SNP Panel RR remained strongly associated with breast cancer diagnosis after multivariable adjustment. Higher BMI was also strongly associated with increased odds of breast cancer diagnosis. Obese women (OR¿=¿2.20, 95% CI 1.05 to 4.58, P¿=¿0.036) had more than twice the odds of cancer diagnosis compared to women with BMI <25 kg/m2. The SNP Panel appeared to have predictive ability among both white and black women.Conclusions Breast cancer risk factors, including BMI and genetic markers are predictive of cancer diagnosis among women with BI-RADS 4 mammograms. Using pre-test risk factors to guide follow-up of abnormal mammograms could reduce the burden of false-positive mammograms.
    Breast cancer research: BCR 01/2015; 17(1):1. DOI:10.1186/s13058-014-0509-4 · 5.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Women at elevated risk for breast cancer are motivated to reduce their risk. Current approaches rely primarily on hormonal intervention. A preventive exercise intervention might address the same hormonal issues, yet have fewer serious side effects and less negative impact on quality of life as compared to prophylactic mastectomy. WISER Sister was a randomized controlled trial which examined effects of two doses of exercise training on endogenous sex hormone exposure, hormonally active breast tissue, and other breast cancer risk factors.
    Contemporary Clinical Trials 01/2015; 41. DOI:10.1016/j.cct.2014.12.016 · 1.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Breast density and single-nucleotide polymorphisms (SNPs) have both been associated with breast cancer risk. To determine the extent to which these two breast cancer risk factors are associated, we investigate the association between a panel of validated SNPs related to breast cancer and quantitative measures of mammographic density in a cohort of Caucasian and African-American women. In this IRB-approved, HIPAA-compliant study, we analyzed a screening population of 639 women (250 African American and 389 Caucasian) who were tested with a validated panel assay of 12 SNPs previously associated to breast cancer risk. Each woman underwent digital mammography as part of routine screening and all were interpreted as negative. Both absolute and percent estimates of area and volumetric density were quantified on a per-woman basis using validated software. Associations between the number of risk alleles in each SNP and the density measures were assessed through a race-stratified linear regression analysis, adjusted for age, BMI, and Gail lifetime risk. The majority of SNPs were not found to be associated with any measure of breast density. SNP rs3817198 (in LSP1) was significantly associated with both absolute area (p = 0.004) and volumetric (p = 0.019) breast density in Caucasian women. In African-American women, SNPs rs3803662 (in TNRC9/TOX3) and rs4973768 (in NEK10) were significantly associated with absolute (p = 0.042) and percent (p = 0.028) volume density respectively. The majority of SNPs investigated in our study were not found to be significantly associated with breast density, even when accounting for age, BMI, and Gail risk, suggesting that these two different risk factors contain potentially independent information regarding a woman's risk to develop breast cancer. Additionally, the few statistically significant associations between breast density and SNPs were different for Caucasian versus African American women. Larger prospective studies are warranted to validate our findings and determine potential implications for breast cancer risk assessment.
    BMC Cancer 01/2015; 15(1):1159. DOI:10.1186/s12885-015-1159-3 · 3.32 Impact Factor
  • Susan M Domchek
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose:Clinical testing for germ-line variation in multiple cancer susceptibility genes is available using massively parallel sequencing. Limited information is available for pretest genetic counseling regarding the spectrum of mutations and variants of uncertain significance in defined patient populations.Methods:We performed massively parallel sequencing using targeted capture of 22 cancer susceptibility genes in 278 BRCA1/2-negative patients with early-onset breast cancer (diagnosed at younger than 40 years of age).Results:Thirty-one patients (11%) were found to have at least one deleterious or likely deleterious variant. Seven patients (2.5% overall) were found to have deleterious or likely deleterious variants in genes for which clinical guidelines exist for management, namely TP53 (4), CDKN2A (1), MSH2 (1), and MUTYH (double heterozygote). Twenty-four patients (8.6%) had deleterious or likely deleterious variants in a cancer susceptibility gene for which clinical guidelines are lacking, such as CHEK2 and ATM. Fifty-four patients (19%) had at least one variant of uncertain significance, and six patients were heterozygous for a variant in MUTYH.Conclusion:These data demonstrate that massively parallel sequencing identifies reportable variants in known cancer susceptibility genes in more than 30% of patients with early-onset breast cancer. However, only few patients (2.5%) have definitively actionable mutations given current clinical management guidelines.Genet Med advance online publication 11 December 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.176.
    Genetics in medicine: official journal of the American College of Medical Genetics 12/2014; DOI:10.1038/gim.2014.176 · 3.92 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: The G1/S checkpoint of the cell cycle is frequently dysregulated in breast cancer (BC). Palbociclib (PD0332991) is an oral inhibitor of CDK4/6. Based upon preclinical/phase I activity, we performed a phase II, single-arm trial of palbociclib in advanced BC. Experimental Design: Eligible patients had histologically confirmed, metastatic BC positive for retinoblastoma (Rb) protein and measureable disease. Palbociclib was given at 125 mg orally on days 1-21 of a 28-day cycle. Primary objectives were tumor response and tolerability. Secondary objectives included progression-free survival (PFS) and assessment of Rb expression/localization, KI-67, p16 loss and CCND1 amplification. Results: 37 patients were enrolled; 84% hormone-receptor (HR)+/Her2-, 5% HR+/Her2+ and 11% HR-/Her2-, with a median of 2 prior cytotoxic regimens. Two patients had partial response (PR) and 5 had stable disease > 6 months for a clinical benefit rate (CBR=PR+6moSD) of 19% overall, 21% in HR+ and 29% in HR+/Her2- who had progressed through > 2 prior lines of hormonal therapy. Median PFS overall was 3.7 months (95% CI 1.9-5.1), but significantly longer for those with HR+ vs. HR- disease (p=0.03) and those who had previously progressed through endocrine therapy for advanced disease (p=0.02). Grade 3/4 toxicities included neutropenia (51%), anemia (5%), and thrombocytopenia (22%). 24% had treatment interruption and 51% had dose reduction, all for cytopenias. No biomarker identified a sensitive tumor population. Conclusion: Single-agent palbociclib is well tolerated and active in patients with endocrine-resistant, hormone-receptor positive, Rb -positive breast cancer. Cytopenias were uncomplicated and easily managed with dose-reduction. Copyright © 2014, American Association for Cancer Research.
    Clinical Cancer Research 12/2014; DOI:10.1158/1078-0432.CCR-14-2258 · 8.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Olaparib is an oral poly (ADP-ribose) polymerase inhibitor with activity in germline BRCA1 and BRCA2 (BRCA1/2) -associated breast and ovarian cancers. We evaluated the efficacy and safety of olaparib in a spectrum of BRCA1/2-associated cancers.
    Journal of Clinical Oncology 11/2014; 33(3). DOI:10.1200/JCO.2014.56.2728 · 17.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
    Cancer Epidemiology Biomarkers & Prevention 10/2014; 24:308-16. DOI:10.1158/1055-9965.EPI-14-0532 · 4.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Inherited mutations in BRCA1 or BRCA2 (BRCA1/2) confer very high risk of breast and ovarian cancers. Genetic testing and counseling can reduce risk and death from these cancers if appropriate preventive strategies are applied, including risk-reducing salpingo-oophorectomy (RRSO) or risk-reducing mastectomy (RRM). However, some women who might benefit from these interventions do not take full advantage of them. We evaluated RRSO and RRM use in a prospective cohort of 1,499 women with inherited BRCA1/2 mutations from 20 centers who enrolled in the study without prior cancer or RRSO or RRM and were followed forward for the occurrence of these events. We estimated the age-specific usage of RRSO/RRM in this cohort using Kaplan-Meier analyses. Use of RRSO was 45 % for BRCA1 and 34 % for BRCA2 by age 40, and 86 % for BRCA1 and 71 % for BRCA2 by age 50. RRM usage was estimated to be 46 % by age 70 in both BRCA1 and BRCA2 carriers. BRCA1 mutation carriers underwent RRSO more frequently than BRCA2 mutation carriers overall, but the uptake of RRSO in BRCA2 was similar after mutation testing and in women born since 1960. RRM uptake was similar for both BRCA1 and BRCA2. Childbearing influenced the use of RRSO and RRM in both BRCA1 and BRCA2. Uptake of RRSO is high, but some women are still diagnosed with ovarian cancer before undergoing RRSO. This suggests that research is needed to understand the optimal timing of RRSO to maximize risk reduction and limit potential adverse consequences of RRSO.
    Breast Cancer Research and Treatment 10/2014; 148(2). DOI:10.1007/s10549-014-3134-0 · 4.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose:Multiplex genetic testing, including both moderate- and high-penetrance genes for cancer susceptibility, is associated with greater uncertainty than traditional testing, presenting challenges to informed consent and genetic counseling. We sought to develop a new model for informed consent and genetic counseling for four ongoing studies. Methods:Drawing from professional guidelines, literature, conceptual frameworks, and clinical experience, a multidisciplinary group developed a tiered-binned genetic counseling approach proposed to facilitate informed consent and improve outcomes of cancer susceptibility multiplex testing.Results:In this model, tier 1 "indispensable" information is presented to all patients. More specific tier 2 information is provided to support variable informational needs among diverse patient populations. Clinically relevant information is "binned" into groups to minimize information overload, support informed decision making, and facilitate adaptive responses to testing. Seven essential elements of informed consent are provided to address the unique limitations, risks, and uncertainties of multiplex testing.Conclusion:A tiered-binned model for informed consent and genetic counseling has the potential to address the challenges of multiplex testing for cancer susceptibility and to support informed decision making and adaptive responses to testing. Future prospective studies including patient-reported outcomes are needed to inform how to best incorporate multiplex testing for cancer susceptibility into clinical practice.Genet Med advance online publication 09 October 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.134.
    Genetics in medicine: official journal of the American College of Medical Genetics 10/2014; DOI:10.1038/gim.2014.134 · 3.92 Impact Factor
  • Fertility and Sterility 09/2014; 102(3):e105. DOI:10.1016/j.fertnstert.2014.07.361 · 4.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND Germline loss-of-function mutations in PALB2 are known to confer a predisposition to breast cancer. However, the lifetime risk of breast cancer that is conferred by such mutations remains unknown. METHODS We analyzed the risk of breast cancer among 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2. The age-specific breast-cancer risk for mutation carriers was estimated with the use of a modified segregation-analysis approach that allowed for the effects of PALB2 genotype and residual familial aggregation. RESULTS The risk of breast cancer for female PALB2 mutation carriers, as compared with the general population, was eight to nine times as high among those younger than 40 years of age, six to eight times as high among those 40 to 60 years of age, and five times as high among those older than 60 years of age. The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval [CI], 9 to 20) by 50 years of age and 35% (95% CI, 26 to 46) by 70 years of age. Breast-cancer risk was also significantly influenced by birth cohort (P < 0.001) and by other familial factors (P = 0.04). The absolute breast-cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25 to 44) for those with no family history of breast cancer to 58% (95% CI, 50 to 66) for those with two or more first-degree relatives with breast cancer at 50 years of age. CONCLUSIONS Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers.
    New England Journal of Medicine 08/2014; 371(6):497-506. DOI:10.1056/NEJMoa1400382 · 54.42 Impact Factor
  • Genetics in medicine: official journal of the American College of Medical Genetics 07/2014; 17(2). DOI:10.1038/gim.2014.85 · 3.92 Impact Factor
  • Susan M Domchek, Katherine L Nathanson
    Genetics in medicine: official journal of the American College of Medical Genetics 07/2014; 16(11). DOI:10.1038/gim.2014.56 · 3.92 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective Few data exist on contraceptive choices in women with cancer. Contraception is challenging for women with cancer, particularly those with breast cancer, who are limited to non-hormonal methods. This study characterized contraceptive use during cancer treatment in a group of reproductive aged women with a recent cancer diagnosis, and assessed the impact of contraceptive counseling on the methods they selected. Study Design Cross-sectional, survey study of reproductive aged women at a large tertiary care health system with a recent cancer diagnosis. Results 107 women completed the survey. 82 women reported 101 contraceptive choices. 27% (27/101) of all methods selected were Tier I/II and 35% (35/101) were Tier III/IV. Only 4 used an IUD. Amongst women reporting sexual activity after diagnosis, 19/71 (27%) reported using Tier I/II methods, 21/71 (30%) reported using Tier III/IV methods, 16/71 (23%) reported abstinence and 10/71 (14%) reported using no method. Factors significantly associated with Tier I/II use in the multivariable model included not having a college degree (OR 0.21, 95%CI 0.05-0.92, p=0.038), intercourse during treatment (OR 5.92, 95%CI 1.48-23.66, p=0.012), non-breast cancer (OR 3.60, 95%CI 1.03-12.64, p=0.046). Report of contraceptive counseling was positively associated with Tier I/II contraceptive use during cancer treatment (OR 6.92, 95%CI 1.14-42.11, p=0.036). Conclusion Reproductive age women diagnosed with cancer underutilized Tier I/II contraceptive agents, especially IUDs. Contraceptive counseling by physicians increases contraceptive use, particularly methods most effective at preventing pregnancy. Implications The study uniquely described the contraceptive practices of over 100 women with cancer. The study sample commonly reported abstinence and use of contraceptive methods with high failure rates. Our data suggest that contraceptive counseling from a healthcare provider may increase use of more effective methods among women with cancer.
    Contraception 07/2014; 90(1). DOI:10.1016/j.contraception.2014.03.002 · 3.09 Impact Factor
  • Tara M Friebel, Susan M Domchek, Timothy R Rebbeck
    [Show abstract] [Hide abstract]
    ABSTRACT: There is substantial variability in cancer risk in women who have inherited a BRCA1 or BRCA2 (BRCA1/2) mutation. Numerous factors have been hypothesized to modify these risks, but studies are of variable quality, and it remains unclear which of these may be of value in clinical risk assessment. PubMed and Web of Science databases were searched for articles published through September 2013. Fixed effects meta-analysis was done using the hazard ratios and/or odds ratios to estimate the pooled effect estimates (ES) and 95% confidence intervals (CIs) to identify factors that are associated with cancer risk modification in BRCA1/2 mutation carriers. We identified 44 nonoverlapping studies that met predefined quality criteria. Sufficient evidence is available to make clinically relevant inferences about a number of cancer risk modifiers. The only variable examined that produced a probable association was late age at first live birth, a meta-analysis showed a decrease in the risk of breast cancer in BRCA1 mutation carriers with women aged 30 years or older vs. women younger than 30 years (ES = 0.65; 95% CI =0.42 to 0.99). The same was shown for women aged 25 to 29 years versus those aged less than 25 years (ES = 0.69; 95% CI = 0.48 to 0.99). Breastfeeding and tubal ligation were associated with reduced ovarian cancer risk in BRCA1 mutation carriers; oral contraceptives were associated with reduced risk among BRCA1/2 mutation carriers. Smoking was associated with increased breast cancer risk in BRCA2 mutation carriers only. Data assessing many potential risk modifiers are inadequate, and many have not been externally validated. Although additional studies are required to confirm some associations, sufficient information is available for some risk factors to be used in risk counseling or lifestyle modification to minimize cancer risk in BRCA1/2 mutation carriers.
    CancerSpectrum Knowledge Environment 05/2014; 106(6). DOI:10.1093/jnci/dju091 · 14.07 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Early and late effects of cancer treatment are of increasing concern with growing survivor populations, but relevant data are sparse. We sought to determine the prevalence and hazard ratio of such effects in breast cancer cases. Women with invasive breast cancer and women with no cancer history recruited for a cancer research cohort completed a mailed questionnaire at a median of 10 years post-diagnosis or matched reference year (for the women without cancer). Reported medical conditions including lymphedema, osteopenia, osteoporosis, and heart disease (congestive heart failure, myocardial infarction, coronary heart disease) were assessed in relation to breast cancer therapy and time since diagnosis using Cox regression. The proportion of women currently receiving treatment for these conditions was calculated. Study participants included 2,535 women with breast cancer and 2,428 women without cancer (response rates 66.0 % and 50.4 %, respectively) Women with breast cancer had an increased risk of lymphedema (Hazard ratio (HR) 8.6; 95 % confidence interval (CI) 6.3-11.6), osteopenia (HR 2.1; 95 % CI 1.8-2.4), and osteoporosis (HR 1.5; 95 % CI 1.2-1.9) but not heart disease, compared to women without cancer Hazard ratios varied by treatment and time since diagnosis. Overall, 49.3 % of breast cancer cases reported at least one medical condition, and at 10 or more years post-diagnosis, 37.7 % were currently receiving condition-related treatment. Responses from survivors a decade following cancer diagnosis demonstrate substantial treatment-related morbidity, and emphasize the need for continued medical surveillance and follow-up care into the second decade post-diagnosis.
    Breast Cancer Research and Treatment 04/2014; 145(1). DOI:10.1007/s10549-014-2928-4 · 4.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    PLoS Genetics 04/2014; 10(4):e1004256. DOI:10.1371/journal.pgen.1004256 · 8.17 Impact Factor

Publication Stats

6k Citations
1,498.79 Total Impact Points


  • 2002–2015
    • University of Pennsylvania
      • • Department of Medicine
      • • "Abramson" Cancer Center
      • • Division of Hematology/Oncology
      • • Department of Biology
      Filadelfia, Pennsylvania, United States
  • 2008–2014
    • William Penn University
      Filadelfia, Pennsylvania, United States
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2013
    • University of Chicago
      • Department of Medicine
      Chicago, IL, United States
  • 2002–2013
    • Hospital of the University of Pennsylvania
      • Department of Medicine
      Philadelphia, Pennsylvania, United States
  • 2012
    • Beth Israel Deaconess Medical Center
      • Division of Hematology/Oncology
      Boston, Massachusetts, United States
    • Treatment Research Institute, Philadelphia PA
      Philadelphia, Pennsylvania, United States
  • 2007–2012
    • Mayo Clinic - Rochester
      • • Department of Health Science Research
      • • Department of Laboratory Medicine & Pathology
      Рочестер, Minnesota, United States
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
    • The Philadelphia Center
      Philadelphia, Pennsylvania, United States
  • 2011
    • University College London
      Londinium, England, United Kingdom
    • IDIBELL Bellvitge Biomedical Research Institute
      Barcino, Catalonia, Spain
  • 2007–2011
    • University of Cambridge
      • Department of Public Health and Primary Care
      Cambridge, ENG, United Kingdom
  • 2010
    • Queensland Institute of Medical Research
      Brisbane, Queensland, Australia
    • Albert Einstein College of Medicine
      New York City, New York, United States
    • University of Michigan
      • Department of Radiation Oncology
      Ann Arbor, MI, United States
  • 2009
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
  • 2007–2009
    • University of Toronto
      • Department of Obstetrics and Gynaecology
      Toronto, Ontario, Canada
  • 2005–2008
    • Creighton University
      Omaha, Nebraska, United States
  • 2006
    • Arcadia University
      Glenside, Pennsylvania, United States
  • 2002–2005
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 2000
    • Massachusetts General Hospital
      Boston, Massachusetts, United States