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A genetic variant in telomerase reverse transcriptase (TERT) modifies cancer risk in Lynch syndrome patients harbouring pathogenic MSH2 variants.

ABSTRACT: Individuals with Lynch syndrome (LS), have an increased risk of developing cancer. Common genetic variants of telomerase reverse transcriptase (TERT) have been associated with a wide range of cancers, including colorectal cancer (CRC) in LS. We combined genotype data from 1881 LS patients, carrying pathogenic variants in MLH1, MSH2 or MSH6, for rs2075786 (G>A, intronic variant), 1207 LS patients for rs2736108 (C>T, upstream variant) and 1201 LS patients for rs7705526 (C>A, intronic variant). The risk of cancer was estimated by heterozygous/homozygous odds ratio (OR) with mixed-effects logistic regression to adjust for gene/gender/country of sample origin considering family identity. The AA genotype of SNP rs2075786 is associated with 85% higher odds at developing cancer compared to GG genotype in MSH2 pathogenic variant carriers (p = 0.0160). Kaplan-Meier analysis also shows an association for rs2075786; the AA allele for MSH2 variant carriers confers risk for earlier diagnosis of LS cancer (log-rank p = 0.0011). We report a polymorphism in TERT to be a possible modifier of disease risk in MSH2 pathogenic variant carriers. The rs2075786 SNP in TERT is associated with a differential risk of developing cancer for MSH2 pathogenic variant carriers. Use of this information has the potential to personalise screening protocols for LS patients.

SUBMITTER: Wiik MU

PROVIDER: S-EPMC8166931 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Helicobacter pylori infection causes chronic gastritis and is the major risk factor of gastric cancer. H. pylori induces a chronic inflammation-producing reactive oxygen species (ROS) which is a source of chromosome instabilities and contributes to the development of malignancy. H. pylori also promotes DNA hypermethylation, known to dysregulate essential genes that maintain genetic stability. The maintenance of telomere length by telomerase is essential for chromosome integrity. Telomerase reverse transcriptase (TERT) is the catalytic component of telomerase activity and an important target during host-pathogen interaction. We aimed to investigate the consequences of H. pylori on the regulation of TERT gene expression and telomerase activity. In vitro, hTERT mRNA levels and telomerase activity were analysed in H. pylori-infected human gastric epithelial cells. In addition, C57BL/6 and INS-GAS mice were used to investigate the influence of H. pylori-induced inflammation on TERT levels. Our data demonstrated that, in vitro, H. pylori inhibits TERT gene expression and decreases the telomerase activity. The exposure of cells to lycopene, an antioxidant compound, restores TERT levels in infected cells, indicating that ROS are implicated in this downregulation. In vivo, fewer TERT-positive cells are observed in gastric tissues of infected mice compared to uninfected, more predominantly in the vicinity of large aggregates of lymphocytes, suggesting an inflammation-mediated regulation. Furthermore, H. pylori appears to downregulate TERT gene expression through DNA hypermethylation as shown by the restoration of TERT transcript levels in cells treated with 5'-azacytidine, an inhibitor of DNA methylation. This was confirmed in infected mice, by PCR-methylation assay of the TERT gene promoter. Our data unraveled a novel way for H. pylori to promote genome instabilities through the inhibition of TERT levels and telomerase activity. This mechanism could play an important role in the early steps of gastric carcinogenesis.

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A genetic variant in telomerase reverse transcriptase (TERT) modifies cancer risk in Lynch syndrome patients harbouring pathogenic MSH2 variants.

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