Identifying novel genetic causes of familial colorectal cancer

Abstract

Colorectal cancer is one of the most frequently diagnosed malignancies world-wide, with up to one-quarter of patients showing familial aggregation of disease, suggesting a strong genetic component. Moreover, a personal or family history of multiple intestinal polyps, including polyposis, confers an increased risk of developing colorectal cancer. However, most of this heritability remains unexplained by known genetic defects.

This thesis focuses on the genetic analysis of patients suspected of hereditary colorectal cancer or polyposis, but negative for causal variants identified in the diagnostic setting. Whole-exome sequencing (WES) was performed in 100 patients to identify novel predisposing variants. Our analyses revealed several genetic mechanisms, including digenic inheritance, where variants in two distinct genes explain the phenotype, a TP53 variant selectively affecting specific protein isoforms, and NPAT as a novel candidate gene for hereditary colorectal cancer.

These studies provide an important foundation for future mechanistic and clinical research, ultimately aiming to improve prevention strategies for individuals with a hereditary predisposition. We are optimistic that, as our understanding of the aetiology of colorectal cancer advances and additional genetic and environmental risk factors are uncovered, more patients from this cohort can be attributed to specific underlying causes.