Dataset Information

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA).

ABSTRACT: BACKGROUND:In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS:We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS:We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION:This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.

SUBMITTER: Osorio A

PROVIDER: S-EPMC2795432 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA).

Osorio A A Milne R L RL Pita G G Peterlongo P P Heikkinen T T Simard J J Chenevix-Trench G G Spurdle A B AB Beesley J J Chen X X Healey S S Neuhausen S L SL Ding Y C YC Couch F J FJ Wang X X Lindor N N Manoukian S S Barile M M Viel A A Tizzoni L L Szabo C I CI Foretova L L Zikan M M Claes K K Greene M H MH Mai P P Rennert G G Lejbkowicz F F Barnett-Griness O O Andrulis I L IL Ozcelik H H Weerasooriya N N Gerdes A-M AM Thomassen M M Cruger D G DG Caligo M A MA Friedman E E Kaufman B B Laitman Y Y Cohen S S Kontorovich T T Gershoni-Baruch R R Dagan E E Jernström H H Askmalm M S MS Arver B B Malmer B B Domchek S M SM Nathanson K L KL Brunet J J Ramón Y Cajal T T Yannoukakos D D Hamann U U Hogervorst F B L FB Verhoef S S Gómez García E B EB Wijnen J T JT van den Ouweland A A Easton D F DF Peock S S Cook M M Oliver C T CT Frost D D Luccarini C C Evans D G DG Lalloo F F Eeles R R Pichert G G Cook J J Hodgson S S Morrison P J PJ Douglas F F Godwin A K AK Sinilnikova O M OM Barjhoux L L Stoppa-Lyonnet D D Moncoutier V V Giraud S S Cassini C C Olivier-Faivre L L Révillion F F Peyrat J-P JP Muller D D Fricker J-P JP Lynch H T HT John E M EM Buys S S Daly M M Hopper J L JL Terry M B MB Miron A A Yassin Y Y Goldgar D D Singer C F CF Gschwantler-Kaulich D D Pfeiler G G Spiess A-C AC Hansen Thomas V O TV Johannsson O T OT Kirchhoff T T Offit K K Kosarin K K Piedmonte M M Rodriguez G C GC Wakeley K K Boggess J F JF Basil J J Schwartz P E PE Blank S V SV Toland A E AE Montagna M M Casella C C Imyanitov E N EN Allavena A A Schmutzler R K RK Versmold B B Engel C C Meindl A A Ditsch N N Arnold N N Niederacher D D Deissler H H Fiebig B B Varon-Mateeva R R Schaefer D D Froster U G UG Caldes T T de la Hoya M M McGuffog L L Antoniou A C AC Nevanlinna H H Radice P P Benítez J J

British journal of cancer 20091117 12

<h4>Background</h4>In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers.<h4>Methods</h4>We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk usi ...[more]

PMID: 19920816

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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.

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.

Dataset Information

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA).

Publications

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA).

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