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

TY - JOUR

T1 - Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk

AU - Carvajal-Carmona, Luis G

AU - O'Mara, Tracy A

AU - Painter, Jodie N

AU - Lose, Felicity A

AU - Dennis, Joe

AU - Michailidou, Kyriaki

AU - Tyrer, Jonathan P

AU - Ahmed, Shahana

AU - Ferguson, Kaltin

AU - Healey, Catherine S

AU - Pooley, Karen

AU - Beesley, Jonathan

AU - Cheng, Timothy

AU - Jones, Angela

AU - Howarth, Kimberley

AU - Martin, Lynn

AU - Gorman, Maggie

AU - Hodgson, Shirley

AU - Wentzensen, Nicholas

AU - Fasching, Peter A

AU - Hein, Alexander

AU - Beckmann, Matthias W

AU - Renner, Stefan P

AU - Dörk, Thilo

AU - Hillemanns, Peter

AU - Dürst, Matthias

AU - Runnebaum, Ingo

AU - Lambrechts, Diether

AU - Coenegrachts, Lieve

AU - Schrauwen, Stefanie

AU - Amant, Frederic

AU - Winterhoff, Boris

AU - Dowdy, Sean C

AU - Goode, Ellen L

AU - Teoman, Attila

AU - Salvesen, Helga B

AU - Trovik, Jone

AU - Njolstad, Tormund S

AU - Werner, Henrica M J

AU - Scott, Rodney J

AU - Ashton, Katie

AU - Proietto, Tony

AU - Otton, Geoffrey

AU - Wersäll, Ofra

AU - Mints, Miriam

AU - Tham, Emma

AU - Hall, Per

AU - Czene, Kamila

AU - Liu, Jianjun

AU - Li, Jingmei

AU - Hopper, John L

AU - Southey, Melissa C

AU - Ekici, Arif B

AU - Ruebner, Matthias

AU - Johnson, Nichola

AU - Peto, Julian

AU - Burwinkel, Barbara

AU - Marme, Frederik

AU - Brenner, Hermann

AU - Dieffenbach, Aida K

AU - Meindl, Alfons

AU - Brauch, Hiltrud

AU - Lindblom, Annika

AU - Depreeuw, Jeroen

AU - Moisse, Matthieu

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Couch, Fergus J

AU - Olson, Janet E

AU - Giles, Graham G

AU - Bruinsma, Fiona

AU - Cunningham, Julie M

AU - Fridley, Brooke L

AU - Børresen-Dale, Anne-Lise

AU - Kristensen, Vessela N

AU - Cox, Angela

AU - Swerdlow, Anthony J

AU - Orr, Nicholas

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - Weber, Rachel Palmieri

AU - Chen, Zhihua

AU - Shah, Mitul

AU - Pharoah, Paul D P

AU - Dunning, Alison M

AU - Tomlinson, Ian

AU - Easton, Douglas F

AU - Spurdle, Amanda B

AU - Thompson, Deborah J

AU - National Study of Endometrial Cancer Genetics Group (NSECG)

AU - Harth, Volker

N1 - Neu angelegt und alte entfernt, da völlig verkorkst! GUW 4.6 Frau Rudoph ist als einizge echt affiliiert: 48 ] Univ Clin Hamburg Eppendorf, Dept Canc Epidemiol, Clin Canc Registry, Hamburg, Germany [ 49 ] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany

PY - 2015/2

Y1 - 2015/2

N2 - 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.

AB - 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.

KW - Chromosomes, Human, Pair 5

KW - Databases, Nucleic Acid

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Genetic Loci

KW - Haplotypes

KW - Humans

KW - Membrane Proteins

KW - Models, Genetic

KW - Neoplasm Proteins

KW - Polymorphism, Single Nucleotide

KW - Promoter Regions, Genetic

KW - Risk Factors

KW - Telomerase

U2 - 10.1007/s00439-014-1515-4

DO - 10.1007/s00439-014-1515-4

M3 - SCORING: Journal article

C2 - 25487306

VL - 134

SP - 231

EP - 245

JO - HUM GENET

JF - HUM GENET

SN - 0340-6717

IS - 2

ER -