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The Spectrum of Germline Nucleotide Variants in Gastric Cancer Patients in the Kyrgyz Republic.

ABSTRACT: Gastric cancer is a major challenge in modern oncology due to its high detection rate and prevalence. While sporadic cases make up the majority of gastric cancer, hereditary gastric cancer is caused by germline mutations in several genes linked to different syndromes. Thus, identifying hereditary forms of gastric cancer is considered crucial globally. A survey study using NGS-based analysis was conducted to determine the frequency of different types of hereditary gastric cancer in the yet-unstudied Kyrgyz population. The study cohort included 113 patients with diagnosed gastric cancer from Kyrgyzstan. The age of patients was 57.6 ± 8.9. Next-generation sequencing analysis of genomic DNA was performed using a custom Roche NimbleGen enrichment panel. The results showed that 6.2% (7/113) of the patients had pathogenic or likely pathogenic genetic variants. Additionally, 3.5% (4/113) of the patients carried heterozygous pathogenic/likely pathogenic variants in high penetrance genes, such as TP53, POLD1, RET, and BRCA2. Moreover, 2.7% (3/113) of the patients carried heterozygous mutations in genes linked to autosomal recessive conditions, specifically PALB2, FANCA, and FANCD2. We have not identified any genetic variants in hereditary GC-associated genes: CDH1, STK11, SMAD4, BMPRIA, APC, MLH1, and others. Our study included patients with sporadic features of GC. The use of recognized criteria (NCCN, Gastric Cancer, Version 2.2022) would increase the number of identified genetic variants in hereditary GC-associated genes. Further research is required to determine the clinical relevance of the genetic variants identified in the current study.

SUBMITTER: Bilyalov A

PROVIDER: S-EPMC10453583 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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The Spectrum of Germline Nucleotide Variants in Gastric Cancer Patients in the Kyrgyz Republic.

Bilyalov Airat A Nikolaev Sergey S Danishevich Anastasiia A Khatkov Igor I Makhmudov Komron K Isakova Zhainagul Z Bakirov Nurbek N Omurbaev Ernis E Osipova Alena A Ramaldanov Ramaldan R Shagimardanova Elena E Kiyasov Andrey A Gusev Oleg O Bodunova Natalia N

Current issues in molecular biology 20230731 8

Gastric cancer is a major challenge in modern oncology due to its high detection rate and prevalence. While sporadic cases make up the majority of gastric cancer, hereditary gastric cancer is caused by germline mutations in several genes linked to different syndromes. Thus, identifying hereditary forms of gastric cancer is considered crucial globally. A survey study using NGS-based analysis was conducted to determine the frequency of different types of hereditary gastric cancer in the yet-unstud ...[more]

PMID: 37623222

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Project description:ObjectiveTo screen and characterize germline variants for E-cadherin (CDH1) in non-hereditary gastric cancer (GC) patients and in subjects at risk of GC.Methods59 GCs, 59 first degree relatives (FDRs) of GC, 20 autoimmune metaplastic atrophic gastritis (AMAGs) and 52 blood donors (BDs) were analyzed for CDH1 by direct sequencing, structural modelling and bioinformatics. Functional impact on splicing was assessed for intronic mutations. E-cadherin/β-catenin immunohistochemical staining and E-cadherin mRNA quantification using RT-PCR were performed.ResultsIn GCs, 4 missense variants (p.G274S; p.A298T; p.T470I; p.A592T), 1 mutation in the 5'UTR (-71C>G) and 1 mutation in the intronic IVS12 (c.1937-13T>C) region were found. First pathogenic effect of p.A298T mutation was predicted by protein 3D modelling. The novel p.G274S mutation showed a no clear functional significance. Moreover, first, intronic IVS12 (c.1937-13T>C) mutation was demonstrated to lead to an aberrant CDH1 transcript with exon 11 deletion. This mutation was found in 2 GCs and in 1 BD. In FDRs, we identified 4 variants: the polymorphic (p.A592T) and 3 mutations in untranslated regions with unidentified functional role except for the 5'UTR (-54G>C) that had been found to decrease CDH1 transcription. In AMAGs, we detected 2 alterations: 1 missense (p.A592T) and 1 novel variant (IVS1 (c.48+7C>T)) without effect on CDH1 splicing. Several silent and polymorphic substitutions were found in all the groups studied.ConclusionsOverall our study improves upon the current characterization of CDH1 mutations and their functional role in GC and in individuals at risk of GC. Mutations found in untranslated regions and data on splicing effects deserve a particular attention like associated with a reduced E-cadherin amount. The utility of CDH1 screening, in addition to the identification of other risk factors, could be useful for the early detection of GC in subjects at risk (i.e. FDRs and AMAGs), and warrants further study.

Project description:BackgroundChronic malnutrition among infants and children continues to represent a global public health concern. The Kyrgyz Republic has achieved rapid declines in stunting over the last 20 y, despite modest increases in gross domestic product per capita.ObjectiveThis study aimed to conduct a systematic, in-depth assessment of national, community, household, and individual drivers of nutrition change and stunting reduction, as well as nutrition-specific and -sensitive policies and programs, in the Kyrgyz Republic.MethodsThis mixed methods study employed 4 inquiry methods, including: 1) a systematic scoping literature review; 2) retrospective quantitative data analyses, including linear regression multivariable hierarchical modeling, difference-in-difference analysis, and Oaxaca-Blinder decomposition; 3) qualitative data collection and analysis; and 4) analysis of key nutrition-specific and -sensitive policies and programs.ResultsStunting prevalence has decreased in the Kyrgyz Republic, however, subnational variations and inequities persist. Child growth Victora curves show improvements in height-for-age z-scores (HAZ) for children in the Kyrgyz Republic between 1997 and 2014, indicating increased intrauterine growth and population health improvements. The decomposition analysis explained 88.9% (0.637 SD increase) of the predicted change in HAZ for children under 3 y (1997-2012). Key factors included poverty (61%), maternal nutrition (14%), paternal education (6%), fertility (6%), maternal age (3%), and wealth accumulation (2%). Qualitative analysis revealed poverty reduction, increased migration and remittances, food security, and maternal nutrition as key drivers of stunting decline. Systematic scoping literature review findings supported quantitative and qualitative results, and indicated that land reforms and improved food security represented important factors. Key nutrition-specific and -sensitive policies and programs implemented involved breastfeeding promotion, social protection schemes, and land and health sector reforms.ConclusionsImprovements in stunting were achieved amidst political and economic changes. Multilevel enablers, including poverty reduction, improved food security, and introduction of land and health reforms have contributed to improvements in health, nutrition, and stunting among children in the Kyrgyz Republic.

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Dataset Information

The Spectrum of Germline Nucleotide Variants in Gastric Cancer Patients in the Kyrgyz Republic.

Publications

The Spectrum of Germline Nucleotide Variants in Gastric Cancer Patients in the Kyrgyz Republic.

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