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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-02

AUTHORS

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 Pooley, Jonathan Beesley, Timothy Cheng, Angela Jones, Kimberley Howarth, Lynn Martin, Maggie Gorman, Shirley Hodgson, National Study of Endometrial Cancer Genetics Group (NSECG), The Australian National Endometrial Cancer Study Group (ANECS), Nicholas Wentzensen, Peter A. Fasching, Alexander Hein, Matthias W. Beckmann, Stefan P. Renner, Thilo Dörk, Peter Hillemanns, Matthias Dürst, Ingo Runnebaum, Diether Lambrechts, Lieve Coenegrachts, Stefanie Schrauwen, Frederic Amant, Boris Winterhoff, Sean C. Dowdy, Ellen L. Goode, Attila Teoman, Helga B. Salvesen, Jone Trovik, Tormund S. Njolstad, Henrica M. J. Werner, Rodney J. Scott, Katie Ashton, Tony Proietto, Geoffrey Otton, Ofra Wersäll, Miriam Mints, Emma Tham, RENDOCAS, Per Hall, Kamila Czene, Jianjun Liu, Jingmei Li, John L. Hopper, Melissa C. Southey, Australian Ovarian Cancer Study (AOCS), Arif B. Ekici, Matthias Ruebner, Nichola Johnson, Julian Peto, Barbara Burwinkel, Frederik Marme, Hermann Brenner, Aida K. Dieffenbach, Alfons Meindl, Hiltrud Brauch, The GENICA Network, Annika Lindblom, Jeroen Depreeuw, Matthieu Moisse, Jenny Chang-Claude, Anja Rudolph, Fergus J. Couch, Janet E. Olson, Graham G. Giles, Fiona Bruinsma, Julie M. Cunningham, Brooke L. Fridley, Anne-Lise Børresen-Dale, Vessela N. Kristensen, Angela Cox, Anthony J. Swerdlow, Nicholas Orr, Manjeet K. Bolla, Qin Wang, Rachel Palmieri Weber, Zhihua Chen, Mitul Shah, Paul D. P. Pharoah, Alison M. Dunning, Ian Tomlinson, Douglas F. Easton, Amanda B. Spurdle, Deborah J. Thompson

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. More... »

PAGES

231-245

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s00439-014-1515-4

    DOI

    http://dx.doi.org/10.1007/s00439-014-1515-4

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1018384724

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/25487306


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