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

被引：30

作者：

Carvajal-Carmona, Luis G. ^{[1
,2
]}

O'Mara, Tracy A. ^{[3
]}

Painter, Jodie N. ^{[3
]}

Lose, Felicity A. ^{[3
]}

Dennis, Joe ^{[4
]}

Michailidou, Kyriaki ^{[4
]}

Tyrer, Jonathan P. ^{[5
]}

Ahmed, Shahana ^{[5
]}

Ferguson, Kaltin ^{[3
]}

Healey, Catherine S. ^{[5
]}

Pooley, Karen ^{[4
]}

Beesley, Jonathan ^{[3
]}

Cheng, Timothy ^{[6
]}

Jones, Angela ^{[6
]}

Howarth, Kimberley ^{[6
]}

Martin, Lynn ^{[6
]}

Gorman, Maggie ^{[6
]}

Hodgson, Shirley ^{[7
]}

Wentzensen, Nicholas ^{[8
]}

Fasching, Peter A. ^{[9
,10
]}

Hein, Alexander ^{[10
]}

Beckmann, Matthias W. ^{[10
]}

Renner, Stefan P. ^{[10
]}

Doerk, Thilo ^{[11
]}

Hillemanns, Peter ^{[12
,13
]}

Duerst, Matthias ^{[14
]}

Runnebaum, Ingo ^{[14
]}

Lambrechts, Diether ^{[15
,16
]}

Coenegrachts, Lieve ^{[17
]}

Schrauwen, Stefanie ^{[17
]}

Amant, Frederic ^{[17
,18
]}

Winterhoff, Boris ^{[19
]}

Dowdy, Sean C. ^{[19
]}

Goode, Ellen L. ^{[20
]}

Teoman, Attila ^{[19
]}

Salvesen, Helga B. ^{[21
,22
]}

Trovik, Jone ^{[21
,22
]}

Njolstad, Tormund S. ^{[21
,22
]}

Werner, Henrica M. J. ^{[21
,22
]}

Scott, Rodney J. ^{[23
,24
,25
]}

Ashton, Katie ^{[23
,25
,26
]}

Proietto, Tony ^{[27
]}

Otton, Geoffrey ^{[27
]}

Wersaell, Ofra ^{[28
]}

Mints, Miriam ^{[28
]}

Tham, Emma ^{[29
]}

Hall, Per ^{[30
]}

Czene, Kamila ^{[30
]}

Liu, Jianjun ^{[31
]}

Li, Jingmei ^{[31
]}

机构：

[1] Univ Calif Davis, Sch Med, Genome Ctr, Davis, CA 95616 USA

[2] Univ Calif Davis, Sch Med, Dept Biochem & Mol Med, Davis, CA 95616 USA

[3] QIMR Berghofer Med Res Inst, Australian Ovarian Canc Study AOCS, Australian Natl Endometrial Canc Study Grp ANECS, Brisbane, Qld, Australia

[4] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England

[5] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England

[6] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[7] St Georges Hosp Med Sch, Dept Clin Genet, London, England

[8] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA

[9] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol Oncol, Los Angeles, CA 90095 USA

[10] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, D-91054 Erlangen, Germany

[11] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany

[12] Hannover Med Sch, Clin Gynaecol, Hannover, Germany

[13] Hannover Med Sch, Clin Obstet, Hannover, Germany

[14] Univ Jena, Jena Univ Hosp, Dept Gynaecol, Jena, Germany

[15] VIB, Vesalius Res Ctr, Leuven, Belgium

[16] Katholieke Univ Leuven, Lab Translat Genet, Dept Oncol, Leuven, Belgium

[17] Katholieke Univ Leuven, Dept Oncol, Leuven, Belgium

[18] Univ Hosp Leuven, Div Gynaecol Oncol, Leuven, Belgium

[19] Mayo Clin, Dept Obstet & Gynecol, Div Gynecol Oncol, Rochester, MN USA

[20] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA

[21] Univ Bergen, Dept Clin Sci, Ctr Cancerbiomarkers, Bergen, Norway

[22] Haukeland Hosp, Dept Obstet & Gynecol, N-5021 Bergen, Norway

[23] John Hunter Hosp, Hunter Med Res Inst, Newcastle, NSW, Australia

[24] John Hunter Hosp, Hunter Area Pathol Serv, Newcastle, NSW, Australia

[25] Univ Newcastle, Sch Biomed Sci & Pharm, Ctr Informat Based Med, Newcastle, NSW 2300, Australia

[26] Univ Newcastle, Sch Biomed Sci & Pharm, Discipline Med Genet, Newcastle, NSW 2300, Australia

[27] Univ Newcastle, Sch Med & Publ Hlth, Newcastle, NSW 2300, Australia

[28] Karolinska Inst, Karolinska Univ Hosp, Dept Womens & Childrens Hlth, Stockholm, Sweden

[29] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden

[30] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[31] Genome Inst Singapore, Singapore, Singapore

[32] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia

[33] Univ Melbourne, Genet Epidemiol Lab, Dept Pathol, Melbourne, Vic, Australia

[34] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[35] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England

[36] London Sch Hyg & Trop Med, London WC1, England

[37] Heidelberg Univ, Dept Gynecol & Obstet, Heidelberg, Germany

[38] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany

[39] German Canc Consortium DKTK, Heidelberg, Germany

[40] Tech Univ Munich, Dept Obstet & Gynecol, Div Tumor Genet, D-80290 Munich, Germany

[41] Univ Tubingen, Dr Margarete Fischer Bosch Inst Clin Pharmacol St, Tubingen, Germany

[42] Deutsch Krebsforschungszentrum DKFZ, Mol Genet Breast Canc, Heidelberg, Germany

[43] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany

[44] Univ Clin Hamburg Eppendorf, Dept Canc Epidemiol, Clin Canc Registry, Hamburg, Germany

[45] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany

[46] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA

[47] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA

[48] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia

[49] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia

[50] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS 66103 USA

来源：

HUMAN GENETICS | 2015年 / 134卷 / 02期

基金：

英国医学研究理事会; 加拿大健康研究院; 美国国家卫生研究院; 澳大利亚国家健康与医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; BREAST-CANCER; FUNCTIONAL VARIATION; TELOMERE LENGTH; COMMON VARIANT; EXPRESSION; TERT; GENE; MICROARRAY;

D O I：

10.1007/s00439-014-1515-4

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 10(-6) to P = 7.7 x 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 x 10(-18), CLPTM1L P = 1.5 x 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.

引用

页码：231 / 245

页数：15

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