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Poster Display session 2

1970 - Identification of a spectrum of germline mutations for hereditary diffuse gastric cancer in the Russian population by next-generation sequencing.

Date

29 Sep 2019

Session

Poster Display session 2

Presenters

IRINA EFIMOVA

Citation

Annals of Oncology (2019) 30 (suppl_5): v253-v324. 10.1093/annonc/mdz247

Authors

I.U. EFIMOVA1, E. Ignatova2, I. Bykov3, A.I. Kalinkin4, A.S. Tanas5, E.A. Alekseeva6, V.V. Strelnikov7, A. Alakunov8, E. Kuznetsova8, M.V. Nemtsova8

Author affiliations

  • 1 Epigenetics Laboratory, Federal State Budgetary Institution "Research Centre for Medical Genetics", 115478 - Moscow/RU
  • 2 Clinical Pharmacology And Chemotherapy, FSBI-N. N. Blokhin Russian Cancer Research Center, 117535 - Moscow/RU
  • 3 Oncosurgery Of The Head And Neck, Breast, Soft Tissue, Skin Cancer, IM Sechenov First Moscow State Medical University, 119991 - Moscow/RU
  • 4 Center Of Master's Programs, IM Sechenov First Moscow State Medical University, 119991 - Moscow/RU
  • 5 Epigenetics, Federal State Budgetary Institution "Research Centre for Medical Genetics", 115478 - Moscow/RU
  • 6 Russia, Research Centre for Medical Genetics, 115478 - Moscow/RU
  • 7 Epigenetics, Research Centre for Medical Genetics, 115478 - Moscow/RU
  • 8 Genetics Laboratory, IM Sechenov First Moscow State Medical University, 119991 - Moscow/RU
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Resources

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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