Molecular Basis of Adenomatous Gastrointestinal Polyposis Syndromes: Role of Pathogenic and Benign Variants in Disease Onset

<b>Background:</b> Colorectal cancer (CRC) is the third most diagnosed type of cancer and the second leading cause of cancer-related death. However, the increase in CRC incidence observed over the last 50 years has been accompanied by an overall reduction in mortality thanks to improved diagnostic strategies, patient follow-up, and more targeted therapies. Gastrointestinal adenomatous polyposis syndromes are a group of hereditary syndromes that predispose individuals to gastrointestinal tumors. These syndromes, characterized by the onset of gastrointestinal adenomas, are genetically heterogeneous. <b>Methods</b>: We analyzed 60 subjects with clinical suspicion or diagnosis of polyposis using next-generation sequencing (NGS). An additional 20 healthy individuals, all negative for pathogenic variants, were included in the study as a control population. We also performed bioinformatic analyses to investigate the hypothesis that benign variants could still be partially destructive, even though they cannot, by themselves, be responsible for the onset of disease. <b>Results:</b> Germline pathogenic variants were identified in 55% (33/60) of affected patients (MUT⁺), while variants of uncertain significance (VUS) were identified in 18.3% of affected patients (11/60). No variants were detected in the remaining 26.7% (16/60) of patients (MUT^-). A genotype-phenotype correlation emerged from this study: MUT⁺ patients exhibited a significantly earlier age of onset and a higher number of polyps compared to VUS or MUT^- patients. Furthermore, Mendelian inheritance was significatively more frequent in MUT⁺ and VUS patients than in MUT^- individuals. Finally, the investigation of benign variants identified an SNP (single nucleotide polymorphism) of the APC gene promoter and a cluster of variants in POLD1, in which bioinformatic analysis predicted altered gene expression. <b>Conclusions:</b> These results suggest that, although MUT^- patients may develop multiple gastrointestinal adenomatous polyps, they are likely to have a familial predisposition rather than a Mendelian disorder. Furthermore, we propose that certain benign variants may be partially deleterious, potentially contributing to disease onset and/or act as phenotypic modifiers, likely through additive effects.