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Telomere structure and maintenance gene variants and risk of five cancer types.

ABSTRACT: Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs ?3.08 × 10-5 ). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk.

SUBMITTER: Karami S

PROVIDER: S-EPMC5198774 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Telomere structure and maintenance gene variants and risk of five cancer types.

Karami Sara S Han Younghun Y Pande Mala M Cheng Iona I Rudd James J Pierce Brandon L BL Nutter Ellen L EL Schumacher Fredrick R FR Kote-Jarai Zsofia Z Lindstrom Sara S Witte John S JS Fang Shenying S Han Jiali J Kraft Peter P Hunter David J DJ Song Fengju F Hung Rayjean J RJ McKay James J Gruber Stephen B SB Chanock Stephen J SJ Risch Angela A Shen Hongbing H Haiman Christopher A CA Boardman Lisa L Ulrich Cornelia M CM Casey Graham G Peters Ulrike U Amin Al Olama Ali A Berchuck Andrew A Berndt Sonja I SI Bezieau Stephane S Brennan Paul P Brenner Hermann H Brinton Louise L Caporaso Neil N Chan Andrew T AT Chang-Claude Jenny J Christiani David C DC Cunningham Julie M JM Easton Douglas D Eeles Rosalind A RA Eisen Timothy T Gala Manish M Gallinger Steven J SJ Gayther Simon A SA Goode Ellen L EL Grönberg Henrik H Henderson Brian E BE Houlston Richard R Joshi Amit D AD Küry Sébastien S Landi Mari T MT Le Marchand Loic L Muir Kenneth K Newcomb Polly A PA Permuth-Wey Jenny J Pharoah Paul P Phelan Catherine C Potter John D JD Ramus Susan J SJ Risch Harvey H Schildkraut Joellen J Slattery Martha L ML Song Honglin H Wentzensen Nicolas N White Emily E Wiklund Fredrik F Zanke Brent W BW Sellers Thomas A TA Zheng Wei W Chatterjee Nilanjan N Amos Christopher I CI Doherty Jennifer A JA

International journal of cancer 20160908 12

Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We p ...[more]

PMID: 27459707

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Project description:BackgroundTelomeres at the ends of eukaryotic chromosomes play a critical role in maintaining the integrity and stability of the genome and participate in the initiation of DNA damage/repair responses.MethodsWe performed a case-control study to evaluate the role of three SNPs (TERT-07, TERT-54 and POT1-03) in telomere maintenance genes previously found to be significantly associated with breast cancer risk. We used sister-sets obtained from the New York site of the Breast Cancer Family Registry (BCFR). Among the 313 sister-sets, there were 333 breast cancer cases and 409 unaffected sisters who were evaluated in the current study. We separately applied conditional logistic regression and generalized estimating equations (GEE) models to evaluate associations between the three SNPs and breast cancer risk within sister-sets. We examined the associations between genotype, covariates and telomere length among unaffected sisters using a GEE model.ResultsWe found no significant associations between the three SNPs in telomere maintenance genes and breast cancer risk by both conditional logistic regression and GEE models, nor were these SNPs significantly related to telomere length. Among unaffected sisters, shortened telomeres were statistically significantly correlated with never hormone replacement therapy (HRT) use. Increased duration of HRT use was significantly associated with reduced telomere length. The means of telomere length were 0.77 (SD = 0.35) for never HRT use, 0.67 (SD = 0.29) for HRT use < 5 yrs and 0.59 (SD = 0.24) for HRT use ≥ 5 yrs after adjusting for age of blood donation and race and ethnicity.ConclusionsWe found that exogenous hormonal exposure was inversely associated with telomere length. No significant associations between genetic variants and telomere length or breast cancer risk were observed. These findings provide initial evidence to understand hormonal exposure in the regulation of telomere length and breast cancer risk but need replication in prospective studies.

Project description:BackgroundTelomeres are repetitive DNA sequences located at the ends of chromosomes, playing a vital role in maintaining chromosomal integrity and stability. Dysregulation of telomeres has been implicated in the development of various cancers, including non-small cell lung cancer (NSCLC), which is the most common type of lung cancer. Genetic variations within telomere maintenance genes may influence the risk of developing NSCLC. The present study aimed to evaluate the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India, and to investigate the relationship between telomere length and NSCLC risk.MethodsWe employed the cost-effective and high-throughput MassARRAY MALDI-TOF platform to assess the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India. Additionally, we used TaqMan genotyping to validate our results. Furthermore, we investigated telomere length variation and its relation to NSCLC risk in the same population using dual-labeled fluorescence-based qPCR.ResultsOur findings revealed significant associations of TERT rs10069690 and POT1 rs10228682 with NSCLC risk (adjusted p-values = 0.019 and 0.002, respectively), while TERF2 rs251796 and rs2975843 showed no significant associations. The TaqMan genotyping validation further substantiated the associations of TERT rs10069690 and rs2242652 with NSCLC risk (adjusted p-values = 0.02 and 0.003, respectively). Our results also demonstrated significantly shorter telomere lengths in NSCLC patients compared to controls (p = 0.0004).ConclusionThis study highlights the crucial interplay between genetic variation in telomere maintenance genes, telomere attrition, and NSCLC risk in the Jammu and Kashmir population of North India. Our findings suggest that TERT and POT1 gene variants, along with telomere length, may serve as potential biomarkers and therapeutic targets for NSCLC in this population. Further research is warranted to elucidate the underlying mechanisms and to explore the potential clinical applications of these findings.

Dataset Information

Telomere structure and maintenance gene variants and risk of five cancer types.

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Telomere structure and maintenance gene variants and risk of five cancer types.

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