Identification and characterization of genes involved in the predisposition to colorectal cancer and polyposis

Resumo

Colorectal cancer (CRC) is a complex disease, one of the cancers with the highest incidence and mortality rates worldwide. While most CRC cases are considered sporadic, 10% of patients present a familial aggregation of the disease. However, only 3 to 5% of them can be attributable to pathogenic germline variants in high-risk cancer genes. During the past years, different next generation sequencing approaches (gene panels, whole-exome sequencing or whole-genome sequencing) have been applied to identify new predisposing genes. Their rapid implementation and easy access have facilitated the generation of a considerable amount of data, increasing the number of candidate variants and genes proposed. Nevertheless, only few of them have been unequivocally associated to hereditary CRC syndromes, mainly associated with polyposis phenotypes. Most proposed candidates lack of independent validation in independent cohorts or functional evidence that confirm their causality. The study of the identified candidate genes in larger cohorts of patients, comparison with controls, or functional evaluation of their presumably pathogenic effects, are crucial to confirm or discard causal association with the disease. Only bona-fide hereditary cancer genes can be implemented into routine genetic diagnostics, and therefore, be useful for the clinical management of carriers. The main purpose of this doctoral thesis is to elucidate the genetic basis of CRC and polyposis missing heritability.