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Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

ABSTRACT: 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.

SUBMITTER: Mulligan AM

PROVIDER: S-EPMC3326552 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

Mulligan Anna Marie AM Couch Fergus J FJ Barrowdale Daniel D Domchek Susan M SM Eccles Diana D Nevanlinna Heli H Ramus Susan J SJ Robson Mark M Sherman Mark M Spurdle Amanda B AB Wappenschmidt Barbara B Lee Andrew A McGuffog Lesley L Healey Sue S Sinilnikova Olga M OM Janavicius Ramunas R Hansen Thomas vO Tv Nielsen Finn C FC Ejlertsen Bent B Osorio Ana A Muñoz-Repeto Iván I Durán Mercedes M Godino Javier J Pertesi Maroulio M Benítez Javier J Peterlongo Paolo P Manoukian Siranoush S Peissel Bernard B Zaffaroni Daniela D Cattaneo Elisa E Bonanni Bernardo B Viel Alessandra A Pasini Barbara B Papi Laura L Ottini Laura L Savarese Antonella A Bernard Loris L Radice Paolo P Hamann Ute U Verheus Martijn M Meijers-Heijboer Hanne E J HE Wijnen Juul J Gómez García Encarna B EB Nelen Marcel R MR Kets C Marleen CM Seynaeve Caroline C Tilanus-Linthorst Madeleine M A MM van der Luijt Rob B RB van Os Theo T Rookus Matti M Frost Debra D Jones J Louise JL Evans D Gareth DG Lalloo Fiona F Eeles Ros R Izatt Louise L Adlard Julian J Davidson Rosemarie R Cook Jackie J Donaldson Alan A Dorkins Huw H Gregory Helen H Eason Jacqueline J Houghton Catherine C Barwell Julian J Side Lucy E LE McCann Emma E Murray Alex A Peock Susan S Godwin Andrew K AK Schmutzler Rita K RK Rhiem Kerstin K Engel Christoph C Meindl Alfons A Ruehl Ina I Arnold Norbert N Niederacher Dieter D Sutter Christian C Deissler Helmut H Gadzicki Dorothea D Kast Karin K Preisler-Adams Sabine S Varon-Mateeva Raymonda R Schoenbuchner Ines I Fiebig Britta B Heinritz Wolfram W Schäfer Dieter D Gevensleben Heidrun H Caux-Moncoutier Virginie V Fassy-Colcombet Marion M Cornelis François F Mazoyer Sylvie S Léoné Mélanie M Boutry-Kryza Nadia N Hardouin Agnès A Berthet Pascaline P Muller Danièle D Fricker Jean-Pierre JP Mortemousque Isabelle I Pujol Pascal P Coupier Isabelle I Lebrun Marine M Kientz Caroline C Longy Michel M Sevenet Nicolas N Stoppa-Lyonnet Dominique D Isaacs Claudine C Caldes Trinidad T de la Hoya Miguel M Heikkinen Tuomas T Aittomäki Kristiina K Blanco Ignacio I Lazaro Conxi C Barkardottir Rosa B RB Soucy Penny P Dumont Martine M Simard Jacques J Montagna Marco M Tognazzo Silvia S D'Andrea Emma E Fox Stephen S Yan Max M Rebbeck Tim T Olopade Olufunmilayo O Weitzel Jeffrey N JN Lynch Henry T HT Ganz Patricia A PA Tomlinson Gail E GE Wang Xianshu X Fredericksen Zachary Z Pankratz Vernon S VS Lindor Noralane M NM Szabo Csilla C Offit Kenneth K Sakr Rita R Gaudet Mia M Bhatia Jasmine J Kauff Noah N Singer Christian F CF Tea Muy-Kheng MK Gschwantler-Kaulich Daphne D Fink-Retter Anneliese A Mai Phuong L PL Greene Mark H MH Imyanitov Evgeny E O'Malley Frances P FP Ozcelik Hilmi H Glendon Gordon G Toland Amanda E AE Gerdes Anne-Marie AM Thomassen Mads M Kruse Torben A TA Jensen Uffe Birk UB Skytte Anne-Bine AB Caligo Maria A MA Soller Maria M Henriksson Karin K Wachenfeldt von Anna vA Arver Brita B Stenmark-Askmalm Marie M Karlsson Per P Ding Yuan Chun YC Neuhausen Susan L SL Beattie Mary M Pharoah Paul D P PD Moysich Kirsten B KB Nathanson Katherine L KL Karlan Beth Y BY Gross Jenny J John Esther M EM Daly Mary B MB Buys Saundra M SM Southey Melissa C MC Hopper John L JL Terry Mary Beth MB Chung Wendy W Miron Alexander F AF Goldgar David D Chenevix-Trench Georgia G Easton Douglas F DF Andrulis Irene L IL Antoniou Antonis C AC

Breast cancer research : BCR 20111102 6

<h4>Introduction</h4>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.<h4>Methods</h4>We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of wh ...[more]

PMID: 22053997

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Project description: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.

Project description:ImportanceThe limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population.ObjectiveTo compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers.Design, setting, and participantsRetrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected.Main outcomes and measuresBRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview.ResultsAmong the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier.Conclusions and relevanceSignificant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.

Dataset Information

Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

Publications

Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

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