Building a hereditary cancer program in Colombia: analysis of germline pathogenic and likely pathogenic variants spectrum in a high-risk cohort.

Abstract

Genetic studies in Latin America have expanded, but further efforts are needed to understand cancer susceptibility genes beyond BRCA1 and BRCA2, especially by characterizing the prevalence and spectrum of pathogenic or likely pathogenic variants (PVs) in the region. This study aimed to determine the frequency of hereditary cancer syndromes (HCS) in Colombians with solid tumors and to characterize the spectrum of PVs. Using data from the Colombia's largest Institutional Hereditary Cancer Program, we included patients aged ≥18 years with solid tumors who met HCS criteria and were offered genetic testing with a 105-cancer gene panel. We calculated the prevalence of PVs and HCS by cancer type (beyond breast) and gene. For patients with breast cancer, we examined genotype-phenotype correlations with molecular subtypes and stratified positivity rates by different genetic testing criteria. Among 769 patients, we identified 216 PVs in 43 genes in 197 patients (26%). Thirty-three PVs were recurrent. Autosomal HCS was found in 21% (160/769) of patients (159 dominant, one recessive), while 5% (37/769) were heterozygous carriers of PVs in autosomal recessive genes. In 42% (321/769) of the cases, only one or more variants of uncertain significance (VUS) were identified, whereas 33% (251/769) had neither PVs nor VUS detected (negative results). HCS prevalence varied by cancer type (11-26%). The triple-negative subtype and bilateral presentation were strong predictors of inherited breast cancer. Our study reveals a significant presence of PVs among high-risk Colombian patients with solid tumors, underscoring the importance of genetic counseling and testing in the region.