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Simple Summary: This study reports the results of genetic testing to identify germline variants in the main genes (APC, BMPR1A, MUTYH, PTEN, SMAD4, STK11) associated with hereditary polyposis syndromes in 75 index cases with colorectal polyps and a personal/family history of cancer that had been referred to genetic counseling at the Medical Genetics Unit of the National Institute of Gastroenterology "Saverio de Bellis", Castellana Grotte, Bari, Italy. In the screened patients, some of which did not meet the recommended eligibility criteria of current National Comprehensive Cancer Network (NCCN) guidelines for genetic testing, we identified 14 pathogenic variants and 6 variants of uncertain significance. Of note, by combining the results of multigene panel tests with the evaluation of patients' clinical phenotype and family history, we were able to confirm the diagnosis of hereditary polyposis syndrome for pathogenic variant carriers and assign them to specific clinical surveillance and management programs. 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. [ABSTRACT FROM AUTHOR]

Background: The minor G-allele of FOXO3 rs2802292 is associated with human longevity. The aim of this study was to test the protective effect of the variant against the association with type 2 Diabetes and NAFLD. Methods: rs2802292 was genotyped in a large population of middle-aged subjects (n = 650) from a small city in Southern Italy. All participants were interviewed to collect information about lifestyle and dietary habits; clinical characteristics were recorded, and blood samples were collected from all subjects. The association between rs2802292 and NAFLD or diabetes was tested using a logistic model and mediation analysis adjusted for covariates. Results: Overall, the results indicated a statistical association between diabetes and rs2802292, especially for the TT genotype (OR = 2.14, 1.01 to 4.53 95% C.I., p = 0.05) or in any case for those who possess the G-allele (OR = 0.45, 0.25 to 0.81 95% C.I., p = 0.008). Furthermore, we found a mediation effect of rs2802292 on diabetes (as mediator) and NAFLD. There is no direct relationship between rs2802292 and NAFLD, but the effect is direct (β = 0.10, −0.003 to 0.12 95% C.I., p = 0.04) on diabetes, but only in TT genotypes. Conclusions: The data on our cohort indicate that the longevity-associated FOXO3 variant may have protective effects against diabetes and NAFLD. [ABSTRACT FROM AUTHOR]

Juvenile polyposis syndrome (JPS) is an inherited autosomal dominant condition that predisposes to the development of juvenile polyps throughout the gastrointestinal (GI) tract, and it poses an increased risk of GI malignancy. Germline causative variants were identified in the SMAD4 gene in a subset (20%) of JPS cases. Most SMAD4 germline genetic variants published to date are missense, nonsense, and frameshift mutations. SMAD4 germline alterations predicted to result in aberrant splicing have rarely been reported. Here, we report two unrelated Italian families harboring two different SMAD4 intronic variants, c.424+5G>A and c.425-9A>G, which are clinically associated with colorectal cancer and/or juvenile GI polyps. In silico prediction analysis, in vitro minigene assays, and RT-PCR showed that the identified variants lead to aberrant SMAD4 splicing via the exonization of intronic nucleotides, resulting in a premature stop codon. This is expected to cause the production of a truncated protein. This study expands the landscape of SMAD4 germline genetic variants associated with GI polyposis and/or cancer. Moreover, it emphasizes the importance of the functional characterization of SMAD4 splicing variants through RNA analysis, which can provide new insights into genetic disease variant interpretation, enabling tailored genetic counseling, management, and surveillance of patients with GI polyposis and/or cancer. [ABSTRACT FROM AUTHOR]

Germline mutations of the ApC gene, which encodes a multidomain protein of 2843 amino acid residues, cause familial adenomatous polyposis (FAp). three FAp clinical variants are correlated with the location of APC mutations: (1) classic FAp with profuse polyposis (>1000 adenomas), associated with mutations from codon 1250 to 1424; (2) attenuated FAp (<100 adenomas), associated with mutations at APC extremities (before codon 157 and after codon 1595); (3) classic FAp with intermediate colonic polyposis (100--1000 adenomas), associated with mutations located in the remaining part of APC. In an effort to decipher the clinical phenotype associated with ApC C-terminal germline truncating mutations in patients with FAp, after screening APC mutations in one family whose members (n=4) developed gastric polyposis, colon oligo- polyposis and desmoid tumours, we performed a literature meta- analysis of clinically characterised patients (n=97) harbouring truncating mutations in ApC C- terminus. the APC distal mutations identified in this study cluster with a phenotype characterised by colon oligo- polyposis, diffuse gastric polyposis and desmoid tumours. In conclusion, we describe a novel FAp clinical variant, which we propose to refer to as Gastric polyposis and Desmoid FAp, that may require tailored management. [ABSTRACT FROM AUTHOR]