Comprehensive Analysis of Germline Variants in Mexican Patients with Hereditary Breast and Ovarian Cancer Susceptibility.

Quezada Urban R1, Díaz Velásquez CE2, Gitler R3, Rojo Castillo MP4, Sirota Toporek M5, Figueroa Morales A6, Moreno García O7, García Esquivel L8, Torres Mejía G9, Dean M10, Delgado Enciso I11, Ochoa Díaz López H12, Rodríguez León F13, Jan V14, Garzón Barrientos VH15, Ruiz Flores P16, Espino Silva PK17, Haro Santa Cruz J18, Martínez Gregorio H19, Rojas Jiménez EA20, Romero Cruz LE21, Méndez Catalá CF22, Álvarez Gómez RM23, Fragoso Ontiveros V24, Herrera LA25, Romieu I26,27, Terrazas LI28,29, Chirino YI30,31, Frecha C32, Oliver J33, Perdomo S34,35, Vaca Paniagua F36,37,38.

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Abstract

Hereditary breast and ovarian cancer syndrome (HBOC) represents 5⁻10% of all patients with breast cancer and is associated with high-risk pathogenic alleles in BRCA1/2 genes, but only for 25% of cases. We aimed to find new pathogenic alleles in a panel of 143 cancer-predisposing genes in 300 Mexican cancer patients with suspicion of HBOC and 27 high-risk patients with a severe family history of cancer, using massive parallel sequencing. We found pathogenic variants in 23 genes, including BRCA1/2. In the group of cancer patients 15% (46/300) had a pathogenic variant; 11% (33/300) harbored variants with unknown clinical significance (VUS) and 74% (221/300) were negative. The high-risk group had 22% (6/27) of patients with pathogenic variants, 4% (1/27) had VUS and 74% (20/27) were negative. The most recurrent mutations were the Mexican founder deletion of exons 9-12 and the variant p.G228fs in BRCA1, each found in 5 of 17 patients with alterations in this gene. Rare VUS with potential impact at the protein level were found in 21 genes. Our results show for the first time in the Mexican population a higher contribution of pathogenic alleles in other susceptibility cancer genes (54%) than in BRCA1/2 (46%), highlighting the high locus heterogeneity of HBOC and the necessity of expanding genetic tests for this disease to include broader gene panels.