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Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk.

ABSTRACT: Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.

SUBMITTER: Carvajal-Carmona LG

PROVIDER: S-EPMC4291520 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk.

Carvajal-Carmona Luis G LG O'Mara Tracy A TA Painter Jodie N JN Lose Felicity A FA Dennis Joe J Michailidou Kyriaki K Tyrer Jonathan P JP Ahmed Shahana S Ferguson Kaltin K Healey Catherine S CS Pooley Karen K Beesley Jonathan J Cheng Timothy T Jones Angela A Howarth Kimberley K Martin Lynn L Gorman Maggie M Hodgson Shirley S Wentzensen Nicholas N Fasching Peter A PA Hein Alexander A Beckmann Matthias W MW Renner Stefan P SP Dörk Thilo T Hillemanns Peter P Dürst Matthias M Runnebaum Ingo I Lambrechts Diether D Coenegrachts Lieve L Schrauwen Stefanie S Amant Frederic F Winterhoff Boris B Dowdy Sean C SC Goode Ellen L EL Teoman Attila A Salvesen Helga B HB Trovik Jone J Njolstad Tormund S TS Werner Henrica M J HM Scott Rodney J RJ Ashton Katie K Proietto Tony T Otton Geoffrey G Wersäll Ofra O Mints Miriam M Tham Emma E Hall Per P Czene Kamila K Liu Jianjun J Li Jingmei J Hopper John L JL Southey Melissa C MC Ekici Arif B AB Ruebner Matthias M Johnson Nichola N Peto Julian J Burwinkel Barbara B Marme Frederik F Brenner Hermann H Dieffenbach Aida K AK Meindl Alfons A Brauch Hiltrud H Lindblom Annika A Depreeuw Jeroen J Moisse Matthieu M Chang-Claude Jenny J Rudolph Anja A Couch Fergus J FJ Olson Janet E JE Giles Graham G GG Bruinsma Fiona F Cunningham Julie M JM Fridley Brooke L BL Børresen-Dale Anne-Lise AL Kristensen Vessela N VN Cox Angela A Swerdlow Anthony J AJ Orr Nicholas N Bolla Manjeet K MK Wang Qin Q Weber Rachel Palmieri RP Chen Zhihua Z Shah Mitul M Pharoah Paul D P PD Dunning Alison M AM Tomlinson Ian I Easton Douglas F DF Spurdle Amanda B AB Thompson Deborah J DJ

Human genetics 20141209 2

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. ...[more]

PMID: 25487306

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Project description:The objective of the present study was to analyze the relationship between genetic polymorphisms of the rs2736098 locus of the telomerase reverse transcriptase (TERT) gene and the rs401681 locus of the cleft lip and palate transmembrane protein 1 (CLPTM1L) gene and the risk of developing lung cancer in males in Jinzhou. A total of 214 lung cancer patients who were admitted in Jinzhou Medical University were analyzed, and 216 healthy males were selected as controls. Venous blood from all subjects and data on relevant risk factors were collected. DNA was extracted from peripheral blood by the phenol-chloroform method. Real-time fluorescent quantitative PCR (TaqMan real-time PCR) was used for DNA amplification. The genotyping results of the genetic polymorphisms of the TERT rs2736098 and CLPTM1L rs401681 loci were detected. The risk of developing lung cancer in the population with the TERT rs2736098 locus carrying the T allele was 1.614 times that with the TERT rs2736098 locus carrying the C allele after adjustment of the age factor. The risk of developing lung cancer in the population carrying the TT mutant genotype and the CT genotype increased significantly compared with that carrying the CC wild genotype [odds ratio (OR)=1.815, 95% CI=1.132-2.957; OR=2.417, 95% CI=1.158-4.943]. Based on a comparison between the combination of the two mutant genotypes (CT+TT) and the wild homozygous genotype (CC), the mutant genotype increased the risk of developing lung cancer (OR=1.955, 95% CI=1.213-3.157). The risk of developing lung cancer in the population with the CLPTM1L rs401681 locus carrying the T allele was 1.399 times that carrying the C allele (OR=1.343, 95% CI=1.035-1.978). The population with the TERT rs2736098 locus carrying the mutant genotype (CT+TT) was associated with the number of tumors (OR=0.553, 95% CI=0.236-0.928). In conclusion, in males, the TERT rs2736098 and CLPTM1L rs401681 T alleles are the susceptibility factors for developing lung cancer. Individuals, including the smoking population, who carry both the TERT rs2736098 and CLPTM1L rs401681 T alleles are more likely to develop lung cancer.

Dataset Information

Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk.

Publications

Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk.

Similar Datasets

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