Clinical Assessment and Genetic Testing for Hereditary Polyposis Syndromes in an Italian Cohort of Patients with Colorectal Polyps

<b>Background</b>: Hereditary polyposis syndromes are clinically and genetically heterogeneous conditions associated with increased colorectal cancer risk. They are classified based on polyp histology, inheritance mode, causal gene, and colonic and extracolonic manifestations. Their diagnosis is challenging due to overlapping and heterogeneous clinical presentations. <b>Methods</b>: A multigene next-generation sequencing panel was used to screen 75 index cases with colorectal polyps and a personal/family history of cancer for key hereditary polyposis-associated genes (<i>APC</i>, <i>BMPR1A</i>, <i>MUTYH</i>, <i>PTEN</i>, <i>SMAD4</i>, and <i>STK11</i>) in order to identify germline genetic variants. <b>Results</b>: In the screened index cases, we found 14 pathogenic variants involving <i>APC</i>, <i>MUTYH</i>, <i>SMAD4</i>, and <i>STK11</i> and 6 variants of uncertain significance involving <i>APC</i>, <i>BMPR1A</i>, and <i>SMAD4</i>. In this cohort, four patients not fulfilling the recommended eligibility criteria of current National Comprehensive Cancer Network (NCCN) guidelines for genetic testing were molecularly diagnosed with a hereditary polyposis syndrome. <b>Conclusions</b>: Our findings indicate that stringent NCCN eligibility criteria for molecular screening may lead to missing some of the patients affected by hereditary polyposis syndromes. This highlights the need for a careful evaluation of patients' clinical manifestations, polyp number, age of polyp onset, and family history to select appropriate candidates for molecular diagnosis of these conditions.