Dataset Information

Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

ABSTRACT: BACKGROUND:Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. METHODS:We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers. RESULTS:There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10(-13) for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 × 10(-14)), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 × 10(-15)). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%). CONCLUSIONS/IMPACT: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis.

SUBMITTER: Mavaddat N

PROVIDER: S-EPMC3272407 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

Mavaddat Nasim N Barrowdale Daniel D Andrulis Irene L IL Domchek Susan M SM Eccles Diana D Nevanlinna Heli H Ramus Susan J SJ Spurdle Amanda A Robson Mark M Sherman Mark M Mulligan Anna Marie AM Couch Fergus J FJ Engel Christoph C McGuffog Lesley L Healey Sue S Sinilnikova Olga M OM Southey Melissa C MC Terry Mary Beth MB Goldgar David D O'Malley Frances F John Esther M EM Janavicius Ramunas R Tihomirova Laima L Hansen Thomas V O TV Nielsen Finn C FC Osorio Ana A Stavropoulou Alexandra A Benítez Javier J Manoukian Siranoush S Peissel Bernard B Barile Monica M Volorio Sara S Pasini Barbara B Dolcetti Riccardo R Putignano Anna Laura AL Ottini Laura L Radice Paolo P Hamann Ute U Rashid Muhammad U MU Hogervorst Frans B FB Kriege Mieke M van der Luijt Rob B RB Peock Susan S Frost Debra D Evans D Gareth DG Brewer Carole C Walker Lisa L Rogers Mark T MT Side Lucy E LE Houghton Catherine C Weaver JoEllen J Godwin Andrew K AK Schmutzler Rita K RK Wappenschmidt Barbara B Meindl Alfons A Kast Karin K Arnold Norbert N Niederacher Dieter D Sutter Christian C Deissler Helmut H Gadzicki Doroteha D Preisler-Adams Sabine S Varon-Mateeva Raymonda R Schönbuchner Ines I Gevensleben Heidrun H Stoppa-Lyonnet Dominique D Belotti Muriel M Barjhoux Laure L Isaacs Claudine C Peshkin Beth N BN Caldes Trinidad T de la Hoya Miguel M Cañadas Carmen C Heikkinen Tuomas T Heikkilä Päivi P Aittomäki Kristiina K Blanco Ignacio I Lazaro Conxi C Brunet Joan J Agnarsson Bjarni A BA Arason Adalgeir A Barkardottir Rosa B RB Dumont Martine M Simard Jacques J Montagna Marco M Agata Simona S D'Andrea Emma E Yan Max M Fox Stephen S Rebbeck Timothy R TR Rubinstein Wendy W Tung Nadine N Garber Judy E JE 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 MM Singer Christian F CF Tea Muy-Kheng MK Rappaport Christine C Mai Phuong L PL Greene Mark H MH Sokolenko Anna A Imyanitov Evgeny E Toland Amanda Ewart AE Senter Leigha L Sweet Kevin K Thomassen Mads M Gerdes Anne-Marie AM Kruse Torben T Caligo Maria M Aretini Paolo P Rantala Johanna J von Wachenfeld Anna A Henriksson Karin K Steele Linda L Neuhausen Susan L SL Nussbaum Robert R Beattie Mary M Odunsi Kunle K Sucheston Lara L Gayther Simon A SA Nathanson Kate K Gross Jenny J Walsh Christine C Karlan Beth B Chenevix-Trench Georgia G Easton Douglas F DF Antoniou Antonis C AC

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20111205 1

<h4>Background</h4>Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.<h4>Methods</h4>We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers.<h4>Results</h4>There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased w ...[more]

PMID: 22144499

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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

Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

Publications

Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

Similar Datasets

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