Abstract A25: Investigating the co-occurrence of potentially pathogenic DNA repair pathways alleles in BRCA1 or BRCA2 mutation carrier women with ovarian cancer.

Abstract Recurrent mutations in BRCA1 and BRCA2, which are genes that play a major role in the homologous recombination (HR) DNA repair pathway, account for a significant proportion of hereditary breast cancer (HBC) and or breast-ovarian cancer (HBOC) families of French Canadian (FC) descent due to common founders. This has facilitated genetic testing for establishing germline mutation carrier status in hereditary cancer clinics in Quebec for offering cancer surveillance and prevention options for women at risk for hereditary breast and other cancers. Recent evidence suggests that rare germline mutations in other members of HR pathway also confer an increased risk to these cancers, and thus could account in part for some of the HBC and HBOC families from the general population found negative for germline BRCA1 and BRCA2 mutations. Interestingly, our group has identified rare potentially pathogenic germline alleles in other DNA repair pathway genes in BRCA1 or BRCA2 mutation carrier FC women with breast cancer from HBC families. This prompted our investigation of the co-occurrence of germline mutations in selected DNA repair genes in BRCA1 or BRCA2 mutation carrier FC women with ovarian cancer. Whole Exome Sequencing (WES) analysis was performed on 15 BRCA1 or BRCA2 mutation carriers from HBOC families with at least two cases of ovarian cancer. Data was analyzed for potentially damaging rare alleles occurring in 178 genes known to be involved in different DNA repair pathways, including BRCA1 and BRCA2. Minor allele frequencies (MAF) were inferred by surveying public databases for genotypes of the general European population: NHLBI GO Exome Sequencing Project (ESP), 1000 Genomes Project (1KG), and The Exome Aggregation Consortium (ExAC). In addition to confirming the BRCA1 and BRCA2 mutations, a total of 23 rare variants with MAF <1% were identified in 21 out of the 178 investigated DNA repair genes; none of these variants were found in the healthy FC cohort (N~200). Eight out of the 23 variants were very rare, each with MAF<0.002%, which is comparable to allele frequencies for the known founder pathogenic BRCA1 and BRCA2 mutations observed in FC carriers. Five variants had no reported MAFs in the public databases. Ten out of the 15 BRCA1 or BRCA2 mutation carriers were each found to carry one to three variants. Five out of the 13 variants were found in genes (POLG, PARP1, FEN1, NUDT1, and OGG1) involved in the Base Excision Repair (BER) pathway: one nonsense, one frameshift, and three missense mutations. One missense and an alternative splicing variant were found in Nucleotide Excision Repair (NER) pathway genes (RAD23A and ERCC2), and two missense variants were found in HR pathway genes (CHEK2 and BRCA1); the variant found in BRCA1 was different from the known pathogenic mutations found in the BRCA1 mutation carriers investigated). The remaining four variants, all conferring missense mutations, were found in genes (POLD1, POLE, and TOPBP1) involved in multiple DNA repair pathways. Interestingly, the identified BRCA1 missense mutation was found in each of two BRCA2 pathogenic mutation carriers, which was predicted to be damaging using prediction software tools for the functional implication of amino acid substitutions (SIFT). This BRCA1 missense mutation was also found in a BRCA1 pathogenic mutation carrier with breast cancer from one of 58 pathogenic BRCA1 or BRCA2 mutation carrier HBC families of FC descent. Although the sample size was limited, our results suggest that BRCA1 or BRCA2 mutation carrier FC women with ovarian cancer also may carry potentially damaging mutations in other DNA repair genes, warranting further research to investigate their biological implications. Citation Format: Wejdan M. Alenezi, Timothee Revil, Dunarel Badescu, Suzanna L. Arcand, Guy Rouleau, Ioannis Ragoussis, Patricia N. Tonin. Investigating the co-occurrence of potentially pathogenic DNA repair pathways alleles in BRCA1 or BRCA2 mutation carrier women with ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A25.

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