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

Abstract

Background: 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. Methods: 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 (APC, BMPR1A, MUTYH, PTEN, SMAD4, and STK11) in order to identify germline genetic variants. Results: In the screened index cases, we found 14 pathogenic variants involving APC, MUTYH, SMAD4, and STK11 and 6 variants of uncertain significance involving APC, BMPR1A, and SMAD4. 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. Conclusions: 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.

Keywords: APC; BMPR1A; MUTYH; SMAD4; STK11; clinical eligibility criteria; genetic testing; hereditary polyposis syndromes; pathogenic variant (PV); variant of uncertain significance (VUS).

Figure 1

Overview of the genetic testing results of the 75 index cases included in this study. (a) Percentage distribution of the index cases with a pathogenic variant (PV), a variant of uncertain significance (VUS), or no identified variant. (b) Percentage distribution of the 14 index cases carrying a PV in a hereditary polyposis-associated gene (APC, MUTYH, SMAD4, and STK11). (c) Percentage distribution of the 6 index cases carrying a VUS in a hereditary polyposis-associated gene (APC, BMPR1A, and MUTYH).

Figure 2

Family pedigree of family 6. Squares indicate men; circles indicate women. Squares and circles with a number inside represent multiple individuals. The arrow indicates the index case. Black-filled symbols denote individuals with cancer, gray-filled symbols indicate individuals with colorectal polyps (CPs), and unfilled symbols correspond to individuals without cancer. Slashed symbols denote dead individuals. The following information is given for specific individuals: clinical manifestations (LUAD = lung adenocarcinoma, BC = breast cancer), age of death (†), age of onset of clinical manifestations, or age at genetic testing (y = years). The zygosity of MUTYH pathogenic variants (PVs) is also shown (MUTHY+/− = heterozygous PV; MUTYH +/+ = compound heterozygous PVs).

Figure 3

Family pedigree of family 9. Squares indicate men; circles indicate women. Squares and circles with a number inside represent multiple individuals. The arrow indicates the index case. Black-filled symbols denote individuals with cancer, and unfilled symbols correspond to individuals without cancer. Slashed symbols denote dead individuals. The following information is given for specific individuals: clinical manifestations (PRAD: prostate adenocarcinoma; HCC: hepatocellular carcinoma; CRC: colorectal cancer; CPs: colorectal polyps), age of onset of clinical manifestations, or age at genetic testing (y = years). The zygosity of MUTYH pathogenic variants (PVs) is also shown (MUTHY+/− = heterozygous PV; MUTYH +/+ = compound heterozygous PVs).