Dataset Information

Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2.

ABSTRACT: Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR)?=?1.03, 95% CI 1.00-1.06, p?=?0.023). There was evidence for heterogeneity in the ORs among studies (I(2)?=?49.3%; p?=?<0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR?=?0.89, 95%CI 0.80-1.00, p?=?0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.

SUBMITTER: Kirchhoff T

PROVIDER: S-EPMC3387216 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2.

Kirchhoff Tomas T Gaudet Mia M MM Antoniou Antonis C AC McGuffog Lesley L Humphreys Manjeet K MK Dunning Alison M AM Bojesen Stig E SE Nordestgaard Børge G BG Flyger Henrik H Kang Daehee D Yoo Keun-Young KY Noh Dong-Young DY Ahn Sei-Hyun SH Dork Thilo T Schürmann Peter P Karstens Johann H JH Hillemanns Peter P Couch Fergus J FJ Olson Janet J Vachon Celine C Wang Xianshu X Cox Angela A Brock Ian I Elliott Graeme G Reed Malcolm W R MW Burwinkel Barbara B Meindl Alfons A Brauch Hiltrud H Hamann Ute U Ko Yon-Dschun YD Broeks Annegien A Schmidt Marjanka K MK Van 't Veer Laura J LJ Braaf Linde M LM Johnson Nichola N Fletcher Olivia O Gibson Lorna L Peto Julian J Turnbull Clare C Seal Sheila S Renwick Anthony A Rahman Nazneen N Wu Pei-Ei PE Yu Jyh-Cherng JC Hsiung Chia-Ni CN Shen Chen-Yang CY Southey Melissa C MC Hopper John L JL Hammet Fleur F Van Dorpe Thijs T Dieudonne Anne-Sophie AS Hatse Sigrid S Lambrechts Diether D Andrulis Irene L IL Bogdanova Natalia N Antonenkova Natalia N Rogov Juri I JI Prokofieva Daria D Bermisheva Marina M Khusnutdinova Elza E van Asperen Christi J CJ Tollenaar Robert A E M RA Hooning Maartje J MJ Devilee Peter P Margolin Sara S Lindblom Annika A Milne Roger L RL Arias José Ignacio JI Zamora M Pilar MP Benítez Javier J Severi Gianluca G Baglietto Laura L Giles Graham G GG Spurdle Amanda B AB Beesley Jonathan J Chen Xiaoqing X Holland Helene H Healey Sue S Wang-Gohrke Shan S Chang-Claude Jenny J Mannermaa Arto A Kosma Veli-Matti VM Kauppinen Jaana J Kataja Vesa V Agnarsson Bjarni A BA Caligo Maria A MA Godwin Andrew K AK Nevanlinna Heli H Heikkinen Tuomas T Fredericksen Zachary Z Lindor Noralane N Nathanson Katherine L KL Domchek Susan M SM Loman Niklas N Karlsson Per P Stenmark Askmalm Marie M Melin Beatrice B von Wachenfeldt Anna A Hogervorst Frans B L FB Verheus Martijn M Rookus Matti A MA Seynaeve Caroline C Oldenburg Rogier A RA Ligtenberg Marjolijn J MJ Ausems Margreet G E M MG Aalfs Cora M CM Gille Hans J P HJ Wijnen Juul T JT Gómez García Encarna B EB Peock Susan S Cook Margaret M Oliver Clare T CT Frost Debra D Luccarini Craig C Pichert Gabriella G Davidson Rosemarie R Chu Carol C Eccles Diana D Ong Kai-Ren KR Cook Jackie J Douglas Fiona F Hodgson Shirley S Evans D Gareth DG Eeles Rosalind R Gold Bert B Pharoah Paul D P PD Offit Kenneth K Chenevix-Trench Georgia G Easton Douglas F DF

PloS one 20120629 6

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether ...[more]

PMID: 22768030

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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.

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

Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2.

Publications

Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2.

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