Comprehensive Germline Genetic Analysis Of Mexican Patients With Predisposition To Inherited Breast Cancer By Massive Parallel Sequencing

Felipe VACA PANIAGUA, Facultad de Estudios Superiores Iztacala, UNAM, Mexico
QUEZADA-URBAN R. 1 , DIAZ VELASQUEZ C. 1 , GITLER R. 2 , ROJO CASTILLO P. 2 , SIROTA TOPOREK M. 2 , FIGUEROA MORALES A. 2 , MORENO GARCIA O. 2 , MAINERO RATCHELOUS F. 3 , DE HOYOS AREVALO S. 3 , DELGADO ENCISO I. 4 , GARZON BARRIENTOS V. 5 , TERRAZAS L. 1

1 Unidad de Biomedicina-Laboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, FES-Iztacala, UNAM, Mexico.
2 Fundacion ALMA
3 Servicio de Oncología Mamaria. Hospital “Dr. Luis Castelazo Ayala”. Gineco 4 IMSS. México.
4 Instituto Estatal de Cancerología de Colima
5 Hospital General de Chilpancingo

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, in the Mexican population the spectrum of inherited breast cancer susceptibility not caused by BRCA1/2 pathogenic alleles has not been explored. To this aim, 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, following inclusion criteria based on the guidelines of the National Comprehensive Cancer Network. In these patients we defined pathogenic variants using data from international databases of normal populations and cancer patients, annotation information and technical parameters. Pathogenic alleles (stopgain/loss, frameshift indels) were found in 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%). Private 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 other pathogenic alleles, suggesting a potential contribution of these VUS to disease susceptibility. In 29 patients we did not find any potential pathogenic variant. This study contributes to identify new susceptibility alleles that can predispose to inherited breast cancer in the Mexican population and highlights the necessity of expanding genetic tests for hereditary breast cancer to broader gene panels. This work was supported by PAPIIT UNAM (IA204215).