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

Wiik, Mariann Unhjem; Evans, Tiffany‐Jane; Belhadj, Sami; Bolton, Katherine; Dymerska, Dagmara; Jagmohan–Changur, Shantie; Capellà, Gabriel; Kurzawski, Grzegorz; Wijnen, Juul T.; Valle, Laura; Vasen, Hans F. A.; Lubiński, Jan; Scott, Rodney J.; Talseth‐Palmer, Bente A.

doi:10.1038/s41598-021-90501-2

Cited by 6 publications

(7 citation statements)

References 39 publications

(45 reference statements)

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“…In particular, two studies confirmed the association of genomic regions 8q23.3 and 11q23.1 with CRC risk in individuals with LS ( 48 , 51 ). A recent study found an association between rs2075786, a SNP of the gene encoding telomerase reverse transcriptase ( TERT ) and cancer risk in individuals with germline MSH2 mutation in a large international cohort ( 50 ). Nevertheless, studies leveraging these results to construct polygenic risk scores in this cohort are still scarce.…”

Section: Discussionmentioning

confidence: 99%

A common genetic variation in GZMB may associate with cancer risk in patients with Lynch syndrome

et al. 2023

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Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is a common genetic predisposition to cancer due to germline mutations in genes affecting DNA mismatch repair. Due to mismatch repair deficiency, developing tumors are characterized by microsatellite instability (MSI-H), high frequency of expressed neoantigens and good clinical response to immune checkpoint inhibitors. Granzyme B (GrB) is the most abundant serine protease in the granules of cytotoxic T-cells and natural killer cells, mediating anti-tumor immunity. However, recent results confirm a diverse range of physiological functions of GrB including that in extracellular matrix remodelling, inflammation and fibrosis. In the present study, our aim was to investigate whether a frequent genetic variation of GZMB, the gene encoding GrB, constituted by three missense single nucleotide polymorphisms (rs2236338, rs11539752 and rs8192917) has any association with cancer risk in individuals with LS. In silico analysis and genotype calls from whole exome sequencing data in the Hungarian population confirmed that these SNPs are closely linked. Genotyping results of rs8192917 on a cohort of 145 individuals with LS demonstrated an association of the CC genotype with lower cancer risk. In silico prediction proposed likely GrB cleavage sites in a high proportion of shared neontigens in MSI-H tumors. Our results propose the CC genotype of rs8192917 as a potential disease-modifying genetic factor in LS.

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Section: Discussionmentioning

confidence: 99%

A common genetic variation in GZMB may associate with cancer risk in patients with Lynch syndrome

et al. 2023

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“…Similar numbers were screened who carried pathogenic variants in MLH1, which attests to the veracity of this study. Two SNPs, rs2075786 and rs2736108 appeared to have an effect on the age of colorectal cancer diagnosis whereas there was no effect observed in MLH1 or MSH6 PV carriers [ 23 ]. It was observed that heterozygote carriers of the rs2736108 SNP were at greater risk of cancer compared to their wildtype counterparts.…”

Section: Problems Associated With Identifying Modifier Genes In Lynch...mentioning

confidence: 99%

“…The number of homozygous carriers of the rs2736108 SNP were minimal (46 in total) with only 27 cancer carriers and 19 cancer free carriers, which negated any meaningful interpretation. Carriers of the minor allele of rs2075786 were more likely to develop cancer at an earlier age compared to heterozygous or wildtype allele carriers [ 23 ].…”

Section: Problems Associated With Identifying Modifier Genes In Lynch...mentioning

confidence: 99%

“…It was not possible to identify any genetic modifiers of disease in MSH6 PV carriers in either of these reports and at this point in time there have been little, if any mention of modifier genes in this subgroup of patients. Notwithstanding, there were some hints within the data reported by Wiis et al 2021, that modifier genes in MSH6 PV carriers may be very different to those identified in MLH1 and MSH2 PV carriers [ 23 ]. Unfortunately, knowledge about any modifiers genes influencing disease risk in MSH6 PV carriers awaits the collection of larger cohorts of patients for any in-depth investigation.…”

Section: Problems Associated With Identifying Modifier Genes In Lynch...mentioning

confidence: 99%

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Modifier genes and Lynch syndrome: some considerations

Scott

2022

Hered Cancer Clin Pract

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Lynch Syndrome (LS) is a highly variable entity with some patients presenting at very young ages with malignancy whereas others may never develop a malignancy yet carry an unequivocal genetic predisposition to disease. The most frequent LS malignancy remains colorectal cancer, a disease that is thought to involve genetic as well as environmental factors in its aetiology. Environmental insults are undeniably associated with cancer risk, especially those imparted by such activities as smoking and excessive alcohol consumption. Notwithstanding, in an inherited predisposition the expected exposures to an environmental insult are considered to be complex and require knowledge about the respective exposure and how it might interact with a genetic predisposition. Typically, smoking is one of the major confounders when considering environmental factors that can influence disease expression on a background of significant genetic risk. In addition to environmental triggers, the risk of developing a malignancy for people carrying an inherited predisposition to disease can be influenced by additional genetic factors that do not necessarily segregate with a disease predisposition allele. The purpose of this review is to examine the current state of modifier gene detection in people with a genetic predisposition to develop LS and present some data that supports the notion that modifier genes are gene specific thus explaining why some modifier gene studies have failed to identify associations when this is not taken into account.

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“…DNA mismatch repair (MMR) genes, are key factors in response to basebase mismatches and small insertion/deletions caused by misincorporation errors during DNA replication (15). Studies indicated that SNPs of specific MMR genes can affect the expression of genes, activity of enzymes and individual repair efficiency to DNA damages (16)(17)(18). As one of the most important MMR genes, MSH2 plays a critical role in repairing mismatched DNA base.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive investigating of MMR gene in hepatocellular carcinoma with chronic hepatitis B virus infection in Han Chinese population

Jin

Sun

et al. 2023

Front. Oncol.

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Hepatocellular carcinoma associated with chronic hepatitis B virus infection seriously affects human health. Present studies suggest that genetic susceptibility plays an important role in the mechanism of cancer development. Therefore, this study focused on single nucleotide polymorphisms (SNPs) of MMR genes associated with HBV-HCC. Five groups of participants were included in this study, which were healthy control group (HC), spontaneous clearance (SC), chronic hepatitis B group (CHB), HBV-related liver cirrhosis group (LC) and HBV-related hepatocellular carcinoma group (HBV-HCC). A total of 3128 participants met the inclusion and exclusion criteria for this study. 20 polymorphic loci on MSH2, MSH3 and MSH6 were selected for genotyping. There were four case-control studies, which were HC vs. HCC, SC vs. HCC, CHB vs. HCC and LC vs. HCC. We used Hardy-Weinberg equilibrium test, unconditional logistic regression, haplotype analysis, and gene-gene interaction for genetic analysis. Ultimately, after excluding confounding factors such as age, gender, smoking and drinking, 12 polymorphisms were found to be associated with genetic susceptibility to HCC. Haplotype analysis showed the risk haplotype GTTT (rs1805355_G, rs3776968_T, rs1428030_C, rs181747_C) was more frequent in the HCC group compared with the HC group. The GMDR analysis showed that the best interaction model was the three-factor model of MSH2-rs1981928, MSH3-rs26779 and MSH6-rs2348244 in SC vs. HCC group (P=0.001). In addition, we found multiplicative or additive interactions between genes in our selected SNPs. These findings provide new ideas to further explore the etiology and pathogenesis of HCC. We have attempted to explain the molecular mechanisms by which certain SNPs (MSH2-rs4952887, MSH3-rs26779, MSH3-rs181747 and MSH3-rs32950) affect genetic susceptibility to HCC from the perspectives of eQTL, TFBS, cell cycle and so on. We also explained the results of haplotypes and gene-gene interactions. These findings provide new ideas to further explore the etiology and pathogenesis of HCC.

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

Cited by 6 publications

References 39 publications

A common genetic variation in GZMB may associate with cancer risk in patients with Lynch syndrome

A common genetic variation in GZMB may associate with cancer risk in patients with Lynch syndrome

Modifier genes and Lynch syndrome: some considerations

Comprehensive investigating of MMR gene in hepatocellular carcinoma with chronic hepatitis B virus infection in Han Chinese population

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