A rare MSH2 variant as a candidate marker for Lynch Syndrome II screening in Tunisia: A case of Diffuse Gastric Carcinoma

Abstract

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.