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Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers.

ABSTRACT: INTRODUCTION:More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. METHODS:We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. RESULTS:The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC)?=?0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC?=?0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC?=?0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. CONCLUSIONS:Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

SUBMITTER: Kuchenbaecker KB

PROVIDER: S-EPMC4406179 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers.

Kuchenbaecker Karoline B KB Neuhausen Susan L SL Robson Mark M Barrowdale Daniel D McGuffog Lesley L Mulligan Anna Marie AM Andrulis Irene L IL Spurdle Amanda B AB Schmidt Marjanka K MK Schmutzler Rita K RK Engel Christoph C Wappenschmidt Barbara B Nevanlinna Heli H Thomassen Mads M Southey Melissa M Radice Paolo P Ramus Susan J SJ Domchek Susan M SM Nathanson Katherine L KL Lee Andrew A Healey Sue S Nussbaum Robert L RL Rebbeck Timothy R TR Arun Banu K BK James Paul P Karlan Beth Y BY Lester Jenny J Cass Ilana I Terry Mary Beth MB Daly Mary B MB Goldgar David E DE Buys Saundra S SS Janavicius Ramunas R Tihomirova Laima L Tung Nadine N Dorfling Cecilia M CM van Rensburg Elizabeth J EJ Steele Linda L v O Hansen Thomas T Ejlertsen Bent B Gerdes Anne-Marie AM Nielsen Finn C FC Dennis Joe J Cunningham Julie J Hart Steven S Slager Susan S Osorio Ana A Benitez Javier J Duran Mercedes M Weitzel Jeffrey N JN Tafur Isaac I Hander Mary M Peterlongo Paolo P Manoukian Siranoush S Peissel Bernard B Roversi Gaia G Scuvera Giulietta G Bonanni Bernardo B Mariani Paolo P Volorio Sara S Dolcetti Riccardo R Varesco Liliana L Papi Laura L Tibiletti Maria Grazia MG Giannini Giuseppe G Fostira Florentia F Konstantopoulou Irene I Garber Judy J Hamann Ute U Donaldson Alan A Brewer Carole C Foo Claire C Evans D Gareth DG Frost Debra D Eccles Diana D Douglas Fiona F Brady Angela A Cook Jackie J Tischkowitz Marc M Adlard Julian J Barwell Julian J Ong Kai-ren KR Walker Lisa L Izatt Louise L Side Lucy E LE Kennedy M John MJ Rogers Mark T MT Porteous Mary E ME Morrison Patrick J PJ Platte Radka R Eeles Ros R Davidson Rosemarie R Hodgson Shirley S Ellis Steve S Godwin Andrew K AK Rhiem Kerstin K Meindl Alfons A Ditsch Nina N Arnold Norbert N Plendl Hansjoerg H Niederacher Dieter D Sutter Christian C Steinemann Doris D Bogdanova-Markov Nadja N Kast Karin K Varon-Mateeva Raymonda R Wang-Gohrke Shan S Gehrig Andrea A Markiefka Birgid B Buecher Bruno B Lefol Cédrick C Stoppa-Lyonnet Dominique D Rouleau Etienne E Prieur Fabienne F Damiola Francesca F Barjhoux Laure L Faivre Laurence L Longy Michel M Sevenet Nicolas N Sinilnikova Olga M OM Mazoyer Sylvie S Bonadona Valérie V Caux-Moncoutier Virginie V Isaacs Claudine C Van Maerken Tom T Claes Kathleen K Piedmonte Marion M Andrews Lesley L Hays John J Rodriguez Gustavo C GC Caldes Trinidad T de la Hoya Miguel M Khan Sofia S Hogervorst Frans B L FB Aalfs Cora M CM de Lange J L JL Meijers-Heijboer Hanne E J HE van der Hout Annemarie H AH Wijnen Juul T JT van Roozendaal K E P KE Mensenkamp Arjen R AR van den Ouweland Ans M W AM van Deurzen Carolien H M CH van der Luijt Rob B RB Olah Edith E Diez Orland O Lazaro Conxi C Blanco Ignacio I Teulé Alex A Menendez Mireia M Jakubowska Anna A Lubinski Jan J Cybulski Cezary C Gronwald Jacek J Jaworska-Bieniek Katarzyna K Durda Katarzyna K Arason Adalgeir A Maugard Christine C Soucy Penny P Montagna Marco M Agata Simona S Teixeira Manuel R MR Olswold Curtis C Lindor Noralane N Pankratz Vernon S VS Hallberg Emily E Wang Xianshu X Szabo Csilla I CI Vijai Joseph J Jacobs Lauren L Corines Marina M Lincoln Anne A Berger Andreas A Fink-Retter Anneliese A Singer Christian F CF Rappaport Christine C Kaulich Daphne Gschwantler DG Pfeiler Georg G Tea Muy-Kheng MK Phelan Catherine M CM Mai Phuong L PL Greene Mark H MH Rennert Gad G Imyanitov Evgeny N EN Glendon Gord G Toland Amanda Ewart AE Bojesen Anders A Pedersen Inge Sokilde IS Jensen Uffe Birk UB Caligo Maria A MA Friedman Eitan E Berger Raanan R Laitman Yael Y Rantala Johanna J Arver Brita B Loman Niklas N Borg Ake A Ehrencrona Hans H Olopade Olufunmilayo I OI Simard Jacques J Easton Douglas F DF Chenevix-Trench Georgia G Offit Kenneth K Couch Fergus J FJ Antoniou Antonis C AC

Breast cancer research : BCR 20141231 6

<h4>Introduction</h4>More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carrier ...[more]

PMID: 25919761

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Project description:INTRODUCTION:Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. METHODS:We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. RESULTS:The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. CONCLUSIONS:The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

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Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers.

Publications

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers.

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