CDH1 and CTNNA1 Genetic Screening in Tunisian Patients with Hereditary Diffuse Gastric Carcinoma

Abstract Background: Mutational screening of the CDH1 gene is a standard treatment for patients who meet the criteria for Hereditary Diffuse Gastric Cancer (HDGC). In this framework, the classification of variants found in this gene is a crucial step for the clinical management of patients at high risk for HDGC. The aim of this study was to identify CDH1 as well as CTNNA1 mutation profiles predisposing to HDGC from Tunisia. Methods: Thirty four cases were included for this purpose with a mean age at diagnosis of 48 years old. We performed Sanger Sequencing for the entire coding sequence of both genes and MLPA (Multiplex Ligation Probe Amplification) assay to investigate large rearrangements of the CDH1 gene. Results: As a result, three cases (8.82%) carried probably pathogenic variants in the CDH1 gene. These variants involves a novel splice alteration, a missense located in exon 14 detected by Sanger Sequencing and a large rearrangement detected by MLPA assay.Conclusion: Our results suggest that the CDH1 p.G761R variant is probably pathogenic and involved in the conformational space shift of the protein. Molecular modeling analysis highlights a putative influence on the conformational properties of the Juxta-Membrane Domain core (JMD) that could result in destabilizing the protein-protein complexes and therefore impacting the downstream pathways. Also, a large deletion from the 5' locus including exons 1 and 2 of the CDH1 gene implicating the signal peptide and a part of the precursor domain of the protein. These findings highlight the critical importance of screening for large CDH1 rearrangements as well as mutations for the management of HDGC families and individuals at high risk for more personalised medicine. We therefore suggest a revision of the status of p.G761R mutation from Variant of Unknown Significance (VUS) to likely pathogenic.