59 research outputs found
Survival after bilateral risk-reducing mastectomy in healthy BRCA1 and BRCA2 mutation carriers
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Effects of chemotherapy on contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers:A nationwide cohort study
AIM: BRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents given for PBC on CBC risk separately in BRCA1 and BRCA2 mutation carriers. PATIENTS AND METHODS: BRCA1 or BRCA2 mutation carriers with an invasive PBC diagnosis from 1990 to 2017 were selected from a Dutch cohort. We estimated cumulative CBC incidence using competing risks analysis. Hazard ratios (HR) for the effect of neo-adjuvant or adjuvant chemotherapy and different chemotherapeutic agents on CBC risk were estimated using Cox regression. RESULTS: We included 1090 BRCA1 and 568 BRCA2 mutation carriers; median follow-up was 8.9 and 8.4 years, respectively. Ten-year cumulative CBC incidence for treatment with and without chemotherapy was 6.7% [95%CI: 5.1â8.6] and 16.7% [95%CI: 10.8â23.7] in BRCA1 and 4.8% [95%CI: 2.7â7.8] and 16.0% [95%CI: 9.3â24.4] in BRCA2 mutation carriers, respectively. Chemotherapy was associated with reduced CBC risk in BRCA1 (multivariable HR: 0.46, 95%CI: 0.29â0.74); a similar trend was observed in BRCA2 mutation carriers (HR: 0.63, 95%CI: 0.29â1.39). In BRCA1, risk reduction was most pronounced in the first 5 years (HR: 0.32, 95%CI: 0.17â0.61). Anthracyclines and the combination of anthracyclines with taxanes were associated with substantial CBC risk reduction in BRCA1 carriers (HR: 0.34, 95%CI: 0.17â0.68 and HR: 0.22, 95%CI: 0.08â0.62, respectively). CONCLUSION: Risk-reducing effects of chemotherapy are substantial for at least 5 years and may be used in personalised CBC risk prediction in any case for BRCA1 mutation carriers
Long-Term Morbidity and Health After Early Menopause Due to Oophorectomy in Women at Increased Risk of Ovarian Cancer:Protocol for a Nationwide Cross-Sectional Study With Prospective Follow-Up (HARMOny Study)
Background: BRCA1/2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) at 35 to 45 years of age. RRSO substantially decreases ovarian cancer risk, but at the cost of immediate menopause. Knowledge about the potential adverse effects of premenopausal RRSO, such as increased risk of cardiovascular disease, osteoporosis, cognitive dysfunction, and reduced health-related quality of life (HRQoL), is limited. Objective: The aim of this study is to assess the long-term health effects of premenopausal RRSO on cardiovascular disease, bone health, cognitive functioning, urological complaints, sexual functioning, and HRQoL in women with high familial risk of breast or ovarian cancer. Methods: We will conduct a multicenter cross-sectional study with prospective follow-up, nested in a nationwide cohort of women at high familial risk of breast or ovarian cancer. A total of 500 women who have undergone RRSO before 45 years of age, with a follow-up period of at least 10 years, will be compared with 250 women (frequency matched on current age) who have not undergone RRSO or who have undergone RRSO at over 55 years of age. Participants will complete an online questionnaire on lifestyle, medical history, cardiovascular risk factors, osteoporosis, cognitive function, urological complaints, and HRQoL. A full cardiovascular assessment and assessment of bone mineral density will be performed. Blood samples will be obtained for marker analysis. Cognitive functioning will be assessed objectively with an online neuropsychological test battery. Results: This study was approved by the institutional review board in July 2018. In February 2019, we included our first participant. As of November 2020, we had enrolled 364 participants in our study. Conclusions: Knowledge from this study will contribute to counseling women with a high familial risk of breast/ovarian cancer about the long-term health effects of premenopausal RRSO. The results can also be used to offer health recommendations after RRSO
Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel
To date, most BC GWASs have been performed Background Polygenic risk score (PRS), calculated in individuals of European (EUR) ancestry, and based on genome-wide association studies (GWASs), the generalisation of EUR-based PRS to other can improve breast cancer (BC) risk assessment. populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.</p
Validation of the BOADICEA model in a prospective cohort of BRCA1/2 pathogenic variant carriers.
Background: No validation has been conducted for the BOADICEA multifactorial breast cancer risk prediction model specifically in BRCA1/2 pathogenic variant (PV) carriers to date. Here, we evaluated the performance of BOADICEA in predicting 5-year breast cancer risks in a prospective cohort of BRCA1/2 PV carriers ascertained through clinical genetic centres. Methods: We evaluated the model calibration and discriminatory ability in the prospective TRANsIBCCS cohort study comprising 1614 BRCA1 and 1365 BRCA2 PV carriers (209 incident cases). Study participants had lifestyle, reproductive, hormonal, anthropometric risk factor information, a polygenic risk score based on 313 SNPs and family history information. Results: The full multifactorial model considering family history together with all other risk factors was well calibrated overall (E/O=1.07, 95% CI: 0.92 to 1.24) and in quintiles of predicted risk. Discrimination was maximised when all risk factors were considered (Harrell's C-index=0.70, 95% CI: 0.67 to 0.74; area under the curve=0.79, 95% CI: 0.76 to 0.82). The model performance was similar when evaluated separately in BRCA1 or BRCA2 PV carriers. The full model identified 5.8%, 12.9% and 24.0% of BRCA1/2 PV carriers with 5-year breast cancer risks of <1.65%, <3% and <5%, respectively, risk thresholds commonly used for different management and risk-reduction options. Conclusion: BOADICEA may be used to aid personalised cancer risk management and decision-making for BRCA1 and BRCA2 PV carriers. It is implemented in the free-access CanRisk tool (https://www.canrisk.org/)
Shared heritability and functional enrichment across six solid cancers
Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe
The predictive ability of the 313 variantâbased polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant
PURPOSE : To evaluate the association between a previously published 313 variantâbased breast cancer (BC) polygenic risk score
(PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.
METHODS : We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402
prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2
(CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall
and ER-specific PRS313 and CBC risk.
RESULTS : For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard
ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06â1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive
PRS313, HR= 1.15, 95% CI (1.07â1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological
characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative
PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes,
respectively.
CONCLUSION : The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the
PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decisionmaking.This work was supported by the Alpe dâHuZes/Dutch Cancer Society (KWF
Kankerbestrijding) project 6253 and Dutch Cancer Society (KWF Kankerbestrijding)
project UL2014-7473. CIMBA: The CIMBA data management and data analysis were
supported by Cancer ResearchâUK grants C12292/A20861, C12292/A11174. G.C.T.
and A.B.S. are NHMRC Research Fellows. iCOGS: the European Communityâs Seventh
Framework Programme under grant agreement number 223175 (HEALTH-F2-2009-
223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/
A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/
A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS
initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112âthe GAME-ON
initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes
of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-
87521), and the Ministry of Economic Development, Innovation and Export Trade
(PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research
Foundation, and the Ovarian Cancer Research Fund. OncoArray: the PERSPECTIVE
and PERSPECTIVE I&I projects funded by the Government of Canada through
Genome Canada and the Canadian Institutes of Health Research, the MinistĂšre de
lâĂconomie, de la Science et de lâInnovation du QuĂ©bec through Genome QuĂ©bec,
and the Quebec Breast Cancer Foundation; the NCI Genetic Associations and
Mechanisms in Oncology (GAME-ON) initiative and Discovery, Biology and Risk of
Inherited Variants in Breast Cancer (DRIVE) project (NIH grants U19 CA148065 and
X01HG007492); and Cancer Research UK (C1287/A10118 and C1287/A16563). BCFR:
UM1 CA164920 from the National Cancer Institute. The content of this paper does
not necessarily reflect the views or policies of the National Cancer Institute or any of
the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does
mention of trade names, commercial products, or organizations imply endorsement
by the US Government or the BCFR. BFBOCC: Lithuania (BFBOCC-LT): Research
Council of Lithuania grant SEN-18/2015. BIDMC: Breast Cancer Research Foundation.
BMBSA: Cancer Association of South Africa (PI Elizabeth J. van Rensburg). BRI-COH: S.
L.N. is partially supported by the Morris and Horowitz Families Professorship. CNIO:
Spanish Ministry of Health PI16/00440 supported by FEDER funds, the Spanish
Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). COH-CCGCRN: Research
reported in this publication was supported by the National Cancer Institute of the
National Institutes of Health under grant number R25CA112486, and RC4CA153828
(PI: J. Weitzel) from the National Cancer Institute and the Office of the Director,
National Institutes of Health. The content is solely the responsibility of the authors
and does not necessarily represent the official views of the National Institutes of
Health. CONSIT TEAM: Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 number
16732) to P. Peterlongo. DEMOKRITOS: European Union (European Social FundâESF)
and Greek national funds through the Operational Program âEducation and Lifelong
Learningâ of the National Strategic Reference Framework (NSRF)âResearch Funding
Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA.
Investing in knowledge society through the European Social Fund. DFKZ: German
Cancer Research Center. EMBRACE: Cancer Research UK Grants C1287/A10118 and
C1287/A11990. D.G.E. and F.L. are supported by an NIHR grant to the Biomedical
Research Centre, Manchester. The Investigators at The Institute of Cancer Research
and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the
Biomedical Research Centre at The Institute of Cancer Research and The Royal
Marsden NHS Foundation Trust. R.E. and E.B. are supported by Cancer Research UK
Grant C5047/A8385. R.E. is also supported by NIHR support to the Biomedical
Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC: A.K.G. was in part funded by the NCI (R01 CA214545), The
University of Kansas Cancer Center Support Grant (P30 CA168524), The Kansas
Institute for Precision Medicine (P20 GM130423), and the Kansas Bioscience Authority
Eminent Scholar Program. A.K.G. is the Chancellors Distinguished Chair in Biomedical
Sciences Professorship. FPGMX: A. Vega is supported by the Spanish Health Research
Foundation, Instituto de Salud Carlos III (ISCIII), partially supported by FEDER funds
through Research Activity Intensification Program (contract grant numbers: INT15/
00070, INT16/00154, INT17/00133), and through Centro de Investigación Biomédica
en Red de Enferemdades Raras CIBERER (ACCI 2016: ER17P1AC7112/2018);
Autonomous Government of Galicia (Consolidation and structuring program:
IN607B), and by the Fundación Mutua Madrileña. The German Consortium for
Hereditary Breast and Ovarian Cancer (GC-HBOC) is funded by the German Cancer
Aid (110837, 70111850, coordinator: Rita K. Schmutzler, Cologne) and the Ministry for
Innovation, Science and Research of the State of North Rhine-Westphalia (#323-
8.0302.16.02-132142). GEMO: initially funded by the French National Institute of
Cancer (INCa, PHRC Ile de France, grant AOR 01 082, 2001-2003, grant 2013-1-BCB-01-
ICH-1), the Association âLe cancer du sein, parlons-en!â Award (2004), the Association
for International Cancer Research (2008-2010), and the Foundation ARC pour la
recherche sur le cancer (grant PJA 20151203365). It also received support from the
Canadian Institute of Health Research for the âCIHR Team in Familial Risks of Breast
Cancerâ program (2008â2013), and the European commission FP7, Project
«Collaborative Ovarian, breast and prostate Gene-environment Study (COGS),
Large-scale integrating project» (2009â2013). GEMO is currently supported by the
INCa grant SHS-E-SP 18-015. GEORGETOWN: The Survey, Recruitment, and Biospecimen
Collection Shared Resource at Georgetown University (NIH/NCI grant P30-
CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research,
and the Nina Hyde Center for Breast Cancer Research. G-FAST: Bruce Poppe is a
senior clinical investigator of FWO. Mattias Van Heetvelde obtained funding from
IWT. HCSC: Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301
CIBERONC from ISCIII (Spain), partially supported by European Regional Development
FEDER funds. HEBCS: Helsinki University Hospital Research Fund, the Finnish Cancer
Society and the Sigrid Juselius Foundation. The HEBON study is supported by the
Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organisation of Scientific Research grant NWO 91109024, the Pink
Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46
and the Transcan grant JTC 2012 Cancer 12-054. HRBCP: Hong Kong Sanatorium and
Hospital, Dr Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation,
National Institute of Health1R 03CA130065, and North California Cancer Center.
HUNBOCS: Hungarian Research Grants KTIA-OTKA CK-80745, NKFI_OTKA K-112228
and TUDFO/51757/2019-ITM. ICO: Contract grant sponsor: Supported by the Carlos III
National Health Institute funded by FEDER fundsâa way to build Europeâ(PI16/00563,
PI19/00553 and CIBERONC); the Government of Catalonia (Pla estratĂšgic de recerca i
innovaciĂł en salut (PERIS) Project MedPerCan, 2017SGR1282 and 2017SGR496); and
CERCA program.IHCC: supported by grant PBZ_KBN_122/P05/2004 and the program
of the Minister of Science and Higher Education under the name âRegional Initiative
of Excellenceâ in 2019â2022 project number 002/RID/2018/19 amount of financing 12
000 000 PLN. ILUH: Icelandic Association âWalking for Breast Cancer Researchâ and by
the Landspitali University Hospital Research Fund. INHERIT: Canadian Institutes of
Health Research for the âCIHR Team in Familial Risks of Breast Cancerâ programâgrant
CRN-87521 and the Ministry of Economic Development, Innovation and Export
Tradeâgrant # PSR-SIIRI-701. IOVHBOCS: Ministero della Salute and â5Ă1000â Istituto
Oncologico Veneto grant. IPOBCS: Liga Portuguesa Contra o Cancro. kConFab: The
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. KOHBRA: the Korea Health Technology R&D Project
through the Korea Health Industry Development Institute (KHIDI), and the National
R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea
(HI16C1127; 1020350; 1420190). KUMC: NIGMS P20 GM130423 (to A.K.G.). MAYO: NIH
grants CA116167, CA192393 and CA176785, an NCI Specialized Program of Research
Excellence (SPORE) in Breast Cancer (CA116201), and a grant from the Breast Cancer
Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast
Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade.
Marc Tischkowitz is supported by the funded by the European Union Seventh
Framework Program (2007Y2013)/European Research Council (Grant No. 310018).
MODSQUAD: MH CZâDRO (MMCI, 00209805) and LM2018125, MEYSâNPS IâLO1413 to LF, and by Charles University in Prague project UNCE204024 (MZ). MSKCC: the
Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer
Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support
Grant/Core Grant (P30 CA008748). NAROD: 1R01 CA149429-01. NCI: the Intramural
Research Program of the US National Cancer Institute, NIH, and by support services
contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc,
Rockville, MD. NICCC: Clalit Health Services in Israel, the Israel Cancer Association and
the Breast Cancer Research Foundation (BCRF), NY. NNPIO: the Russian Foundation
for Basic Research (grants 17-00-00171, 18-515-45012 and 19-515-25001). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative
Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA
37517) and the Intramural Research Program, NCI. OSUCCG: Ohio State University
Comprehensive Cancer Center. PBCS: supported by the âFondazione Pisa per la
Scienza, project nr. 127/2016. Maria A Caligo was supported by the grant: ân. 127/16
Caratterizzazione delle varianti missenso nei geni BRCA1/2 per la valutazione del
rischio di tumore al senoâ by Fondazione Pisa, Pisa, Italy; SEABASS: Ministry of
Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/
06) and Cancer Research Initiatives Foundation. SMC: the Israeli Cancer Association.
SWE-BRCA: the Swedish Cancer Society. UCHICAGO: NCI Specialized Program of
Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996,
1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the
Entertainment Industry Fund National Womenâs Cancer Research Alliance and the
Breast Cancer research Foundation. O.I.O. is an ACS Clinical Research Professor. UCLA:
Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research
Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive
Cancer Center. UKFOCR: Cancer Research h UK. UPENN: Breast Cancer Research
Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for
BRCA. UPITT/MWH: Hackers for Hope Pittsburgh. VFCTG: Victorian Cancer Agency,
Cancer Australia, National Breast Cancer Foundation. WCP: B.Y.K. is funded by the
American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and
the National Center for Advancing Translational Sciences (NCATS), grant
UL1TR000124.https://www.gimjournal.org/am2023Genetic
Mendelian randomisation study of height and body mass index as modiïŹers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers
BACKGROUND : Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown.
METHODS : We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS : Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94â1.23). Height-GS showed similar results (HRâ=â1.02, 95% CI: 0.85â1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HRâ=â1.25 (95% CI: 1.06â1.48) and HRâ=â1.59 (95% CI: 1.08â2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteractionâ<â0.05).
CONCUSION : Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.https://www.nature.com/bjc2020-06-19hj2020Genetic
Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers
Abstract
Introduction
Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).
Methods
To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.
Results
Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).
Conclusions
The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers
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