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, Luis G ×
O'Mara, Tracy A
Painter, Jodie N
Lose, Felicity A
Dennis, Joe
Michailidou, Kyriaki
Tyrer, Jonathan P
Ahmed, Shahana
Ferguson, Kaltin
Healey, Catherine S
Pooley, Karen
Beesley, Jonathan
Cheng, Timothy
Jones, Angela
Howarth, Kimberley
Martin, Lynn
Gorman, Maggie
Hodgson, Shirley
National Study of Endometrial Cancer Genetics Group (NSECG)
The Australian National Endometrial Cancer Study Group (ANECS)
Wentzensen, Nicholas
Fasching, Peter A
Hein, Alexander
Beckmann, Matthias W
Renner, Stefan P
Dörk, Thilo
Hillemanns, Peter
Dürst, Matthias
Runnebaum, Ingo
Lambrechts, Diether
Coenegrachts, Lieve
Schrauwen, Stefanie
Amant, Frederic
Winterhoff, Boris
Dowdy, Sean C
Goode, Ellen L
Teoman, Attila
Salvesen, Helga B
Trovik, Jone
Njolstad, Tormund S
Werner, Henrica M J
Scott, Rodney J
Ashton, Katie
Proietto, Tony
Otton, Geoffrey
Wersäll, Ofra
Mints, Miriam
Tham, Emma
Hall, Per
Czene, Kamila
Liu, Jianjun
Li, Jingmei
Hopper, John L
Southey, Melissa C
Australian Ovarian Cancer Study (AOCS)
Ekici, Arif B
Ruebner, Matthias
Johnson, Nichola
Peto, Julian
Burwinkel, Barbara
Marme, Frederik
Brenner, Hermann
Dieffenbach, Aida K
Meindl, Alfons
Brauch, Hiltrud
The GENICA Network
Lindblom, Annika
Depreeuw, Jeroen
Moisse, Matthieu
Chang-Claude, Jenny
Rudolph, Anja
Couch, Fergus J
Olson, Janet E
Giles, Graham G
Bruinsma, Fiona
Cunningham, Julie M
Fridley, Brooke L
Børresen-Dale, Anne-Lise
Kristensen, Vessela N
Cox, Angela
Swerdlow, Anthony J
Orr, Nicholas
Bolla, Manjeet K
Wang, Qin
Weber, Rachel Palmieri
Chen, Zhihua
Shah, Mitul
Pharoah, Paul D P
Dunning, Alison M
Tomlinson, Ian
Easton, Douglas F
Spurdle, Amanda B
Thompson, Deborah J #
Issue Date: Feb-2015
Publisher: Springer-Verlag
Series Title: Human Genetics vol:134 issue:2 pages:231-45
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.
ISSN: 0340-6717
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Translational Genetics (Vesalius Research Center) (+)
Gynaecological Oncology
× corresponding author
# (joint) last author

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