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Influence of the hTERT rs2736100 polymorphism on telomere length in gastric cancer.

ABSTRACT: To investigate the functional consequences of rs2736100 polymorphism in telomere length and examine its link to gastric cancer risk.Telomere length and human telomerase reverse transcriptase (hTERT) mRNA expression were measured in 35 gastric cancer tissues and 5 cell lines and correlated to rs2736100 polymorphism. The relationship between rs2736100 polymorphism and the risk of gastric cancer were examined in 243 gastric cancer patients and 246 healthy individuals.The rs2736100 A allele carrier is closely associated with reduced hTERT mRNA expression and shortened telomere length in gastric cancer tissue and cell lines. When gastric cancers were stratified by histological subtype, telomere length and hTERT mRNA levels were significantly increased in those with the C/C genotype in intestinal-type gastric cancer, but not in diffuse-type gastric cancer. Interestingly, there was no significant difference in the genotype and allele frequencies of the rs2736100 polymorphism between the patients with gastric cancer and healthy controls.The rs2736100 polymorphism of the hTERT gene is involved in the regulation of hTERT expression and telomere length, but not in the risk of gastric cancer.

SUBMITTER: Choi BJ

PROVIDER: S-EPMC4541384 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Influence of the hTERT rs2736100 polymorphism on telomere length in gastric cancer.

Choi Byung Joon BJ Yoon Jung Hwan JH Kim Olga O Choi Won Suk WS Nam Suk Woo SW Lee Jung Young JY Park Won Sang WS

World journal of gastroenterology 20150801 31

<h4>Aim</h4>To investigate the functional consequences of rs2736100 polymorphism in telomere length and examine its link to gastric cancer risk.<h4>Methods</h4>Telomere length and human telomerase reverse transcriptase (hTERT) mRNA expression were measured in 35 gastric cancer tissues and 5 cell lines and correlated to rs2736100 polymorphism. The relationship between rs2736100 polymorphism and the risk of gastric cancer were examined in 243 gastric cancer patients and 246 healthy individuals.<h4 ...[more]

PMID: 26309358

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Project description:BACKGROUND:The rs2736100 single nucleotide polymorphism (SNP) is located in the intron 2 of human telomerase reverse transcriptase (hTERT) gene. Recent genome-wide association studies (GWAS) have consistently supported the strong association between this SNP and risk for multiple cancers. Given the important role of the hTERT gene and this SNP in cancer biology, we hypothesize that rs2736100 may also confer susceptibility to anti-cancer drug sensitivity. In this study we aim to investigate the correlation between the rs2736100 genotype and the responsiveness to anti-cancer agents in the NCI-60 cancer cell panel. METHODS AND MATERIALS:The hTERT rs2736100 was genotyped in the NCI-60 cancer cell lines. The relative telomere length (RTL) of each cell line was quantified using real-time PCR. The genotype was then correlated with publically available drug sensitivity data of two agents with telomerase-inhibition activity: Geldanamycin (HSP90 inhibitor) and RHPS4/BRACO19 (G-quadruplex stabilizer) as well as additional 110 commonly used agents with established mechanism of action. The association between rs2736100 and mutation status of TP53 gene was also tested. RESULTS:The C allele of the SNP was significantly correlated with increased sensitivity to RHPS4/BRACO19 with an additive effect (r = -0.35, p = 0.009) but not with Geldanamycin. The same allele was also significantly associated with sensitivity to antimitotic agents compared to other agents (p = 0.003). The highest correlation was observed between the SNP and paclitaxel (r = -0.36, p = 0.005). The telomere length was neither associated with rs2736100 nor with sensitivity to anti-cancer agents. The C allele of rs2736100 was significantly associated with increased mutation rate in TP53 gene (p = 0.004). CONCLUSION:Our data suggested that the cancer risk allele of hTERT rs2736100 polymorphism may also affect the cancer cell response to both TERT inhibitor and anti-mitotic agents, which might be attributed to the elevated telomerase-independent activity of hTERT, as well as the increased risk for TP53 gene mutagenesis conferred by the polymorphism. Detailed mechanisms need to be further investigated.

Project description:Hypertrophic and atrophic scars are the effect of a dysregulated wound-healing process in genetically predisposed individuals. The genetic predisposition has acquired significant attention due to the diverse phenotype of pathological scarring in individuals with a positive personal and family history. Recent studies have identified telomere shortening and decreased hTERT activity in pathological scarring, proposing the rs2736100 variant of human telomerase reverse transcriptase (hTERT) gene as a valuable variant gene candidate. We examined the scarring process in 71 female patients who had undergone Caesarean section and developed hypertrophic and atrophic scars with the objective to investigate the role of single nucleotide polymorphism (SNP) rs2736100 in pathological scarring. Genotyping was performed using RT-PCR and follow-up included the Patient Observer Scar Assessment Scale (POSAS) and SCAR scales. Comparative analysis for mean POSAS value between the check-ups at 3 and 6 months revealed a statistical decreased difference of 1.71 points [95% confidence interval (CI), 0.4-2.89; P=0.01], while SCAR highlighted a decreased difference of 0.670 (95% CI, -0.04-1.38; P=0.055). The C variant allele revealed a borderline statistical value for the risk of developing pathological scarring (OR=1.44; 95% CI, 0.876-1.332: P=0.066). In our study a pre-conceptional body mass index (BMI) >25 kg/m2 was statistically associated with pathological scarring. The Fitzpatrick type 4 phototype displayed an increased frequency for the heterozygous genotype in the current study, and it was demonstrated that dark skin tone was associated with abnormal scar formation. Our study investigated the role of hTERT gene variant rs2736100 in hypertrophic and atrophic scarring in a Caucasian population group. We report a borderline statistically significant value for the variant C allele of hTERT SNP for the risk of developing pathological scarring in female patients that had undergone Caesarean section.

Dataset Information

Influence of the hTERT rs2736100 polymorphism on telomere length in gastric cancer.

Publications

Influence of the hTERT rs2736100 polymorphism on telomere length in gastric cancer.

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