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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, LG; O'Mara, TA; Painter, JN; Lose, FA; Dennis, J; Michailidou, K; Tyrer, JP; Ahmed, S; Ferguson, K; Healey, CS; et al. 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 (2015) Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk. Human Genetics, 134 (2). pp. 231-245. ISSN 1432-1203 https://doi.org/10.1007/s00439-014-1515-4
SGUL Authors: Hodgson, Shirley Victoria

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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.

Item Type: Article
Additional Information: © The Author(s) 2014. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
Keywords: Genetics & Heredity, 0604 Genetics, 1104 Complementary And Alternative Medicine, 1114 Paediatrics And Reproductive Medicine
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: Human Genetics
ISSN: 1432-1203
Language: eng
Dates:
DateEvent
February 2015Published
PubMed ID: 25487306
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/107363
Publisher's version: https://doi.org/10.1007/s00439-014-1515-4

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