Expanding the genetic landscape of colorectal polyposis: progress and challenges

The study by Dos Santos et al marks a significant advancement in understanding the genetics of colorectal polyposis, particularly within the underrepresented Brazilian population. Utilizing whole-exome sequencing in 27 patients with unexplained polyposis, the researchers identified 16 candidate genes in 44.4% of cases-an impressive outcome given strict exclusion criteria. Many identified variants were linked to the Wnt/β-catenin signaling pathway, reinforcing their biological relevance. However, the study underscores key challenges in genomic medicine, especially the gap between gene discovery and clinical application. A substantial proportion of variants (60.1%) were classified as of uncertain significance, and the absence of functional validation or segregation analysis limits clinical interpretation. Notably, the potential for oligogenic inheritance complicates traditional monogenic models of hereditary cancer risk. The study’s focus on a genetically diverse Brazilian cohort emphasizes the need for population-specific genomic resources and interpretation guidelines. Moving forward, functional studies, including organoid models, loss-of-heterozygosity analyses, and genotype-phenotype correlations, are essential to validate findings. Clinically, discovering novel candidate genes may inform future screening and testing protocols, though careful consideration is needed to manage uncertain results. Overall, the study represents a critical step in polyposis genetics, highlighting both progress made and the work still required for clinical translation.