Metadata supporting Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer

This metadata record describes the data generated and analysed in the study "Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer". The study investigates genetic survival associations in pathogenic variant carriers from Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), genotyped on the OncoArray. Data availability and sourcesA subset of the genotype data that support the findings of this study is publicly available via dbGaP https://identifiers.org/dbgap:phs001321.v1.p1 CIMBA 1000 Genomes-imputed genotype data is protected in accordance with the informed consent received from the study participants and therefore cannot be made publicly available. Requests for data can be made to the CIMBA Data Access Coordination Committee. DACC approval is required to access data from the BCFR-ON, EMBRACE, GC-HBOC, HEBCS, HEBON, IHCC, IPOBCS, MCGILL, and OUH studies Phenotype data is stored in a relational database and an output would be a text file. Imputed genotype data can be requested in the QCTOOL dosage format (https://www.well.ox.ac.uk/~gav/qctool_v2/documentation/genotype_file_formats.html), which has been used in these analyses The contact for data access requests is Lesley McGuffog ([email protected]), Data Manager, Department of Public Health and Primary Care, University of Cambridge Newly discovered survival SNPs were characterized in silico utilizing data from the 1000 genomes and Encode projects as integrated in databases LDlink, RegulomeDB and GeneCards. Candidate genes’ mRNA expression and patient survival was tested in the METABRIC data in European Genome-phenome Archive: EGAD00010000434 (1,302 breast cancer patients). BCAC survival summary results are available from the University of Cambridge BCAC site All summary results will be made available on the CIMBA website upon publication of the related article: http://cimba.ccge.medschl.cam.ac.uk The data that support each table and figure in the related article are summarised in the excel file in this data record. BackgroundThis study investigates the survival of women carrying germline pathogenic BRCA1 or BRCA2 variants. These are the two most important genes linked to breast cancer susceptibility. The great variation in survival rates between tumors with similar characteristics and stage suggests a heritable component, e.g. genetic differences in metastatic potential sensitivity to adjuvant therapy or host factors, like tumor microenvironment interaction, immune surveillance, and efficiency in drug metabolism. Both candidate gene and genome-wide approaches have been employed to find genetic determinants patient prognosis and treatment outcome prediction. Participants women of European ancestry diagnosed with invasive breast cancer before the age of 70 years, enrolled in studies participating in CIMBA. CIMBA studies included in analysis if sufficient follow-up data are available, at least 15 study subjects at risk during the time when five events occurred. Patients were followed from the diagnosis of the first primary breast cancer until death of any causeand censored after 15 years or when lost from follow-up Supplementary table 1 of the related article lists all CIMBA studies, characteristics, sample and cohort sizes. Overall sample sizes: 21 studies for carrier of BRCA1 variants (n = 3,008) 15 studies for carriers of BRCA2 variants (n = 2,009)

Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Abstract Background BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). Methods We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. Results Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10−5) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor–positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15–21.80] and progesterone receptor–positive (OR 5.04; 95 % CI 3.17–8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10−12). Conclusions On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management

Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Abstract Background BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). Methods We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. Results Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10−5) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor–positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15–21.80] and progesterone receptor–positive (OR 5.04; 95 % CI 3.17–8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10−12). Conclusions On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management