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, Pooley K, Beesley J, Cheng T, Jones A, Howarth K, Martin L, Gorman M, Hodgson S, Wentzensen N, Fasching P, Hein A, Beckmann M, Renner S, Doerk T, Hillemanns P, Duerst 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 HMJ, Scott RJ, Ashton K, Proietto T, Otton G, Wersaell O, Mints M, Tham E, Hall P, Czene K, Liu J, Li J, Hopper JL, Southey MC, Ekici AB, Rübner M, Johnson N, Peto J, Burwinkel B, Marme F, Brenner H, Dieffenbach AK, Meindl A, Brauch H, Lindblom A, Depreeuw J, Moisse M, Chang-Claude J, Rudolph A, Couch FJ, Olson JE, Giles GG, Bruinsma F, Cunningham JM, Fridley BL, Borresen-Dale AL, Kristensen VN, Cox A, Swerdlow AJ, Orr N, Bolla MK, Wang Q, Weber RP, Chen Z, Shah M, Pharoah PDP, Dunning AM, Tomlinson I, Easton DF, Spurdle AB, Thompson DJ (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Book Volume: 134

Pages Range: 231-45

Journal Issue: 2

DOI: 10.1007/s00439-014-1515-4

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.

Authors with CRIS profile

Involved external institutions

London School of Hygiene and Tropical Medicine United Kingdom (GB) Ruprecht-Karls-Universität Heidelberg Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Mayo Clinic United States (USA) (US) The University of Melbourne Australia (AU) Cancer Council Victoria Australia (AU) University of Kansas (KU) United States (USA) (US) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) University of Sheffield United Kingdom (GB) The Institute of Cancer Research (ICR) United Kingdom (GB) University of Cambridge United Kingdom (GB) Duke University United States (USA) (US) University of South Florida (USF) United States (USA) (US) University of Oxford United Kingdom (GB) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) University of California Davis (UCDAVIS) United States (USA) (US) St George's Hospital United Kingdom (GB) National Cancer Institute (NCI) United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Friedrich-Schiller-Universität Jena Germany (DE) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) University of Bergen / Universitetet i Bergen Norway (NO) John Hunter Hospital Australia (AU) University of Newcastle (UoN) Australia (AU) Karolinska Institute Sweden (SE) Genome Institute of Singapore Singapore (SG) Technische Universität München (TUM) Germany (DE) Eberhard Karls Universität Tübingen Germany (DE)

How to cite

APA:

Carvajal-Carmona, L.G., O'Mara, T.A., Painter, J.N., Lose, F.A., Dennis, J., Michailidou, K.,... Thompson, D.J. (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), 231-45. https://dx.doi.org/10.1007/s00439-014-1515-4

MLA:

Carvajal-Carmona, Luis G., et al. "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 (2015): 231-45.

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