Abstract 2545: Identification of germline pathogenic alleles in 143 cancer predisposing genes in Mexican patients with hereditary breast cancer by massive parallel sequencing

Abstract

Breast cancer is the neoplastic disease with the highest incidence and mortality worldwide and nearly 10% of the cases are due to inherited pathogenic alleles in cancer predisposing genes such as BRCA1 and BRCA2. However, the spectrum of inherited breast cancer susceptibility not caused by BRCA1/2 pathogenic alleles has not been explored in the Mexican population. In this work we evaluated the presence of germline pathogenic alleles in the coding sequence and splice sites of 143 cancer susceptibility genes in 69 Mexican female patients with cancer that were selected for family cancer history. Inclusion criteria followed the guidelines of the National Comprehensive Cancer Network for Genetic/Familial High-Risk Assessment of Breast and Ovarian Cancer. Data from international databases of normal populations and cancer patients, as well as annotation information and technical parameters were used to define pathogenic variants. The genes with the highest frequency of pathogenic alleles (stopgain/loss, frameshift indels) were BRCA1 (8.7%, 6/69), BRCA2 (2.9%, 2/69), FANCC (2.9%), MSR1 (2.9%), FANCL (1.4%, 1/69), SDHB (1.4%) and TSC2 (1.4%). New or rare missense variants with unknown clinical significance (VUS), but defined as pathogenic in ClinVar or by algorithms assessing evolutionary conservation and deleterious structural changes at protein level, were found in single patients in the genes AIP, ANTXR1, APC, ATR, CD96, CYP21A2, ERCC3, ERCC6, FANCA, FANCB, FANCE, LIG4, LYST, MSH6, MSR1, MTAP, PDE11A, PDGFRA, PMS2, POLE, PTCH1, RAD50, RHBDF2, RUNX1 and WRN. These patients did not have pathogenic alleles, suggesting a potential contribution of these VUS to disease susceptibility. This work contributes to identify new susceptibility alleles that can predispose to hereditary breast cancer in the Mexican population. Further studies need to be conducted to define the clinical impact of the VUS identified here, which together with international efforts will better define genetic susceptibility to breast cancer. This work was supported by the National Autonomous University of Mexico, PAPIIT (IA204215). Citation Format: Felipe Vaca-Paniagua, Rosalía Quezada-Urban, Clara Estela Díaz-Velásquez, Rina Gitler, María Patricia Rojo-Castillo, Max Sirota-Toporek, Andrea Figueroa-Morales, Oscar Moreno-García, Fernando Mainero-Ratchelous, Lizzette Sabrina De Hoyos-Arévalo, Ivan Delgado-Enciso, Victor Hugo Garzón-Barrientos, Luis Ignacio Terrazas. Identification of germline pathogenic alleles in 143 cancer predisposing genes in Mexican patients with hereditary breast cancer by massive parallel sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2545.