Short rare hTERT-VNTR2-2nd alleles are associated with prostate cancer susceptibility and influence gene expression

Abstract

BackgroundThe hTERT (human telomerase reverse transcriptase) gene contains five variable number tandem repeats (VNTR) and previous studies have described polymorphisms for hTERT-VNTR2-2nd. We investigated how allelic variation in hTERT-VNTR2-2nd may affect susceptibility to prostate cancer.MethodsA case-control study was performed using DNA from 421 cancer-free male controls and 329 patients with prostate cancer. In addition, to determine whether the VNTR polymorphisms have a functional consequence, we examined the transcriptional levels of a reporter gene linked to these VNTRs and driven by the hTERT promoter in cell lines.ResultsThree new rare alleles were detected from this study, two of which were identified only in cancer subjects. A statistically significant association between rare hTERT-VNTR2-2nd alleles and risk of prostate cancer was observed [OR, 5.17; 95% confidence interval (CI), 1.09-24.43; P = 0.021]. Furthermore, the results indicated that these VNTRs inserted in the enhancer region could influence the expression of hTERT in prostate cancer cell lines.ConclusionsThis is the first study to report that rare hTERT VNTRs are associated with prostate cancer predisposition and that the VNTRs can induce enhanced levels of hTERT promoter activity in prostate cancer cell lines. Thus, the hTERT-VNTR2-2nd locus may function as a modifier of prostate cancer risk by affecting gene expression.

A polymorphic minisatellite region of BORIS regulates gene expression and its rare variants correlate with lung cancer susceptibility

“…Moreover, there are also several reports indicating that minisatellite polymorphisms can influence gene expression. 16 , 17 , 24 , 25 , 26 , 27 , 28 …”

“…Similar results for transcriptional regulation by minisatellite fragments were previously reported with H-Ras , IL-1α, IGF2 , MUC6 and TERT genes. 16 , 17 , 24 , 25 , 26 Minisatellites of IL-1α, MUC6 and TERT may control gene expression in cancer cell lines, although these are located in the intronic regions of genes. 16 , 17 We suggest that BORIS –MS2, located in the promoter region, differentially regulates the gene transcription in cancer cells and normal cells.…”

“…In addition, it is the fourth most common cancer in females worldwide, based on GLOBOCAN 2008 estimates, 15 and it is a major public health problem in Korea. Because some minisatellite alleles are associated with human diseases, 16 , 17 we investigated the relationship between cancer predisposition and minisatellite variants in BORIS 6 , 12 and revealed increased susceptibility in young patients with breast cancer containing short rare minisatellite alleles of BORIS -MS2. To determine whether allelic variation in BORIS minisatellites influences susceptibility to lung cancer, a case–control study was performed using a PCR-based method.…”

Frequency of <b><i>TERT</i></b> Promoter Mutations in Prostate Cancer

“…These VNTRs were also discussed as having an enhancer function for gene transcription. In vitro studies on PrCa cell lines analyzing the activity of the TERT promoter in combination with different VNTR variants clearly showed an increased luciferase activity for the VNTR2-2nd variants [22,23] . These effects might also be expected for TERT expression and could also increase the individual risk for PrCa.…”

Medical genetics and epigenetics of telomerase

“…Additional genome‐wide association studies found this region to be associated with increased risk for both pancreatic cancer and lung adenocarcinoma [99–104]. Unlike the studies involving breast cancer, an increased risk of prostate cancer was found to be associated with at least one hTERT variation that influences telomerase expression [105, 106]. Other studies have linked cancer risk and telomerase SNP for several cancers including the following: bladder cancer [106, 107], ovarian cancer [108] and cervix cancer [106].…”