Abstract
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.
Highlights
Gastric Carcinoma (GC) is the fifth most common cancer worldwide, with approximately one million new cases registered in 2018 (5.7%) and a wide variation in geographical distribution
We identified a large pathogenic germline deletion and two likely pathogenic variants in the CDH1 gene, as predicted by in silico analysis and molecular modeling
10 to 20% of pathogenic variants are found in the CDH1 gene for families meeting the IGCLC testing criteria [35,36], which is partially consistent with our results, as we found pathogenic and likely pathogenic CDH1 variants in 13.64% of Hereditary Diffuse Gastric Cancer (HDGC) meeting clinical criteria patients
Summary
Gastric Carcinoma (GC) is the fifth most common cancer worldwide, with approximately one million new cases registered in 2018 (5.7%) and a wide variation in geographical distribution. It represents the third leading cause of death from cancer worldwide, causing. Gastric tumors are histologically and genetically heterogeneous, likely because of the exposure of populations to different environmental risk factors and different genetic predispositions. Despite a decline in incidence and mortality, the burden of GC remains relatively high [3]. Incidence predominates in populations from certain geographic regions and socioeconomic groups [4,5]. High-incidence areas include East Asia, Eastern Europe, Central and South
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
