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BACKGROUND Inherited syndromic forms of digestive cancers with age occurrence before 50 seem to be relatively in higher proportions in Tunisia suggesting genetic susceptibility. Several syndromic forms are known to predispose to early onset gastric tumors such as Hereditary Diffuse Gastric Cancer (HDGC) and Lynch Syndrome (LS). LS II is an extracolonic cancer syndrome characterized by a tumor spectrum including gastric cancer (GC). In the current work, our main aim was to identify the mutational spectrum underlying the genetic predisposition to diffuse gastric tumors occurring in a Tunisian family suspected with both HDGC and LS II syndromes. PATIENTS AND METHODS The index case was a woman diagnosed with Diffuse Gastric Carcinoma (DGC) fulfilling the international guidelines for both HDGC and LSII syndromes. Genomic DNA was used for the search of CDH1 and CTNNA1 germ mutations. We performed, also a DNA repair custom panel targeting candidate genes recovering the four DNA repair systems. Structural bioinformatics analysis was conducted to predict the effect of the revealed mutations. RESULTS No deleterious variants have been identified neither in CDH1 nor in CTNNA1 coding and their flanking regions. DNA repair genes panel screening identified two variants: a rare MSH2 c.728G > A classified as a variant with uncertain significance and a novel FANCD2 variant c.1879G > T. The structural prediction model of MSH2 mutation and electrostatic potential calculation showed for the first time that MSH2 c.728G > A is likely pathogenic and is involved in the MSH2-MLH1 complex stability. This mutation appears to affect the MSH2-MLH1 complex as well as DNA-complex stability. The c.1879G > T FANCD2 variant was predicted to destabilize the protein structure. CONCLUSIONS Our results showed that MSH2 p.R243Q variant is likely pathogenic and is involved in the MSH2-MLH1 complex stability with a putative impact on the binding with MLH1 by disrupting the electrostatic potential suggesting the revision of its status from VUS to likely pathogenic. This variant seems to be a shared variant in Mediterranean region. These findings emphasize the importance of testing DNA repair genes for patients diagnosed with DGC with suspicion of LSII as well as colorectal cancer allowing better clinical surveillance for more personalized medicine.

Several syndromic forms of digestive cancers are known to predispose to early-onset gastric tumors such as Hereditary Diffuse Gastric Cancer (HDGC) and Lynch Syndrome (LS). LSII is an extracolonic cancer syndrome characterized by a tumor spectrum including gastric cancer (GC). In the current work, our main aim was to identify the mutational spectrum underlying the genetic predisposition to diffuse gastric tumors occurring in a Tunisian family suspected of both HDGC and LS II syndromes. We selected the index case "JI-021", which was a woman diagnosed with a Diffuse Gastric Carcinoma and fulfilling the international guidelines for both HDGC and LSII syndromes. For DNA repair, a custom panel targeting 87 candidate genes recovering the four DNA repair pathways was used. Structural bioinformatics analysis was conducted to predict the effect of the revealed variants on the functional properties of the proteins. DNA repair genes panel screening identified two variants: a rare

Mutational screening of the CDH1 gene is a standard treatment for patients who fulfill Hereditary Diffuse Gastric Cancer (HDGC) testing criteria. 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 our study was to identify CDH1 as well as CTNNA1 mutational profiles predisposing to HDGC in Tunisia. Thirty-four cases were included for this purpose. We performed Sanger sequencing for the entire coding region of both genes and MLPA (Multiplex Ligation Probe Amplification) assays to investigate large rearrangements of the CDH1 gene. As a result, three cases, all with the HDGC inclusion criteria (8.82% of the entire cohort), carried pathogenic and likely pathogenic variants of the CDH1 gene. These variants involve a novel splicing alteration, a missense c.2281G > A detected by Sanger sequencing, and a large rearrangement detected by MLPA. No pathogenic CTNNA1 variants were found. The large rearrangement is clearly pathogenic, implicating a large deletion of two exons. The novel splicing variant creates a cryptic site. The missense variant is a VUS (Variant with Uncertain Significance). With ACMG (American College of Medical Genetics and Genomics) classification and the evidence available, we thus suggest a revision of its status to likely pathogenic. Further functional studies or cosegregation analysis should be performed to confirm its pathogenicity. In addition, molecular exploration will be needed to understand the etiology of the other CDH1- and CTNNA1-negative cases fulfilling the HDGC inclusion criteria.

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.