Abstract 1970
Background
Gastric cancer is the fifth most common malignancy in the world and the third leading cause of cancer death. Approximately 1–3% of gastric cancers are hereditary. Mutations of CDH1,the gene encoding E-cadherin, are the most common germline mutations detected in gastric cancer and cause hereditary diffuse gastric cancer (HDGC) syndrome. However, there has been no research previously conducted to identify candidate genes for predisposition to hereditary gastric cancer in the Russian population. The purpose of our research was to fill this gap.
Methods
For this study, we collected specimens of the venous blood of 40 patients (age up to 50 years) diagnosed with diffuse gastric cancer, and 80 gastric cancer tumor samples. To define the mutation in these patients we have used NGS with two panels -an Ion AmpliSeq Cancer Hot spot Panel v2, widely used for the analysis of «hot spots» in cancer related genes, and an in-house panel developed for sequencing the genes involved in gastric carcinogenesis (BMPR1A, SMAD4, CDH1, TP53, STK11, PTEN). All found mutations were verified in DNA obtained from peripheral blood lymphocytes, using polymerase chain reaction followed by Sanger sequencing.
Results
In total, with two panels, we have identified 16 genetic germline variants with exceptionally low general population frequencies (no higher than 0.00004 according to the gnomAD database), and 4 genetic variants that have never been reported previously. We detected 6 deleterious mutations in CDH1 gene. All found mutations were missense mutations (A2512G:p.S838G, c.G1234A:p.V412I, .G2635A:p.G879S, c.C8G:p.P3R, c.C670T:p.R224C). Among these 6 mutations, one (c.A907c:pT303P) was newly discovered in this study. Other deleterious germline variants were found in APC, CDKN2B, STK11, MET, SMO and two in RB1 genes. The mean age at diagnosis of gastric cancer patients with mutation was 46,1.
Conclusions
Identifying mutation carriers in families is extremely important. The identification of germline CDH1 mutations offers the opportunity for potentially lifesaving prophylactic gastrectomy, which is the standard of care for these individuals.
Clinical trial identification
Editorial acknowledgement
This work was supported by Russian Foundation for Basic Research (project No. 18-015-00333), Russian Foundation for Basic Research (project No. 18-29-09020).
Legal entity responsible for the study
The authors.
Funding
Russian Foundation for Basic Research (project No. 18-015-00333), Russian Foundation for Basic Research (project No. 18-29-09020).
Disclosure
All authors have declared no conflicts of interest.
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