Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk
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Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk. / 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; 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; Ekici, Arif B; Ruebner, Matthias; Johnson, Nichola; Peto, Julian; Burwinkel, Barbara; Marme, Frederik; Brenner, Hermann; Dieffenbach, Aida K; Meindl, Alfons; Brauch, Hiltrud; 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; National Study of Endometrial Cancer Genetics Group (NSECG).
in: HUM GENET, Jahrgang 134, Nr. 2, 02.2015, S. 231-45.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -