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

Luis G Carvajal-Carmona, Tracy A O'Mara, Jodie N Painter, Felicity A Lose, Joe Dennis, Kyriaki Michailidou, Jonathan P Tyrer, Shahana Ahmed, Kaltin Ferguson, Catherine S. Healey, Karen A Pooley, Jonathan Beesley, Timothy Cheng, Angela Jones, Kimberley Howarth, Lynn Martin, Maggie Gorman, Shirley Hodgson, Nicolas Wentzensen, Peter FaschingAlexander Hein, Matthias Beckmann, Stefan P Renner, Thilo Dork, Peter Hillemanns, Matthias Durst, Ingo B Runnebaum, Diether Lambrechts, Lieve Coenegrachts, Stefanie Schrauwen, Frederic J Amant, Boris Winterhoff, Sean C Dowdy, Ellen L Goode, Attila Teoman, Helga Birgitte Salvesen, Jone Trovik, Tormund S Njolstad, Henrica Maria Johanna Werner, Rodney J Scott, Katie Ashton, Anthony Proietto, Geoffrey Otton, Ofra Wersall, Miriam Mints, Emma Tham, Per Hall, Kamila Czene, Jianjun Liu, Jingmei Li, John L Hopper, Melissa Caroline Southey, Arif B Ekici, Matthias Ruebner, Nichola Johnson, Julian Peto, Barbara Burwinkel, Frederik Marme, Hermann Brenner, Aida Karina Dieffenbach, Alfons Meindl, Hiltrud Brauch, Annika Lindblom, Jeroen Depreeuw, Matthieu Moisse, Jenny Chang-Claude, Anja Rudolph, Fergus J Couch, Janet E Olson, Graham G Giles, Fiona Bruinsma, Julie Cunningham, Brooke Fridley, Anne-Lise Borresen-Dale, Vessela Kristensen, Angela Cox, Anthony J Swerdlow, Nicholas Orr, Manjeet Bolla, Qin Wang, Rachel Palmieri Weber, Zhihua Chen, Mitul Shah, Paul D P Pharoah, Alison M Dunning, Ian P Tomlinson, Douglas F Easton, Amanda B Spurdle, Deborah J Thompson

Research output: Contribution to journalArticleResearchpeer-review

29 Citations (Scopus)


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 (TERTP = 1.5 ? 10-18, CLPTM1LP = 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.
Original languageEnglish
Pages (from-to)231-245
Number of pages15
JournalHuman Genetics
Issue number2
Publication statusPublished - 2015

Cite this