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Title: Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk.
Authors: Carvajal-Carmona LG,  O'Mara TA,  Painter JN,  Lose FA,  Dennis J,  Michailidou K,  Tyrer JP,  Ahmed S,  Ferguson K,  Healey CS,  Pooley K,  Beesley J,  Cheng T,  Jones A,  Howarth K,  Martin L,  Gorman M,  Hodgson S,  National Study of Endometrial Cancer Genetics Group (NSECG),  Australian National Endometrial Cancer Study Group (ANECS),  Wentzensen N,  Fasching PA,  Hein A,  Beckmann MW,  Renner SP,  Dörk T,  Hillemanns P,  Dürst M,  Runnebaum I,  Lambrechts D,  Coenegrachts L,  Schrauwen S,  Amant F,  Winterhoff B,  Dowdy SC,  Goode EL,  Teoman A,  Salvesen HB,  Trovik J,  Njolstad TS,  Werner HM,  Scott RJ,  Ashton K,  Proietto T,  Otton G,  Wersäll O,  Mints M,  Tham E,  RENDOCAS,  Hall P,  Czene K,  Liu J,  Li J,  Hopper JL,  Southey MC,  Australian Ovarian Cancer Study (AOCS),  Ekici AB,  Ruebner M,  Johnson N,  Peto J,  Burwinkel B,  Marme F,  Brenner H,  Dieffenbach AK,  Meindl A,  Brauch H,  GENICA Network,  Lindblom A,  Depreeuw J,  Moisse M,  Chang-Claude J,  Rudolph A,  Couch FJ,  Olson JE,  Giles GG,  Bruinsma F,  Cunningham JM,  Fridley BL,  Børresen-Dale AL,  Kristensen VN,  Cox A,  Swerdlow AJ,  Orr N,  Bolla MK,  Wang Q,  Weber RP,  Chen Z,  Shah M,  Pharoah PD,  Dunning AM,  Tomlinson I,  Easton DF,  Spurdle AB,  Thompson DJ
Journal: Hum Genet
Date: 2015 Feb
Branches: CGB
PubMed ID: 25487306
PMC ID: PMC4291520
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.