A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3

被引：465

作者：

Tomlinson, Ian P. M. ^{[1
]}

Webb, Emily ^{[2
]}

Carvajal-Carmona, Luis ^{[1
]}

Broderick, Peter ^{[2
]}

Howarth, Kimberley ^{[1
]}

Pittman, Alan M. ^{[2
]}

Spain, Sarah ^{[1
]}

Lubbe, Steven ^{[2
]}

Walther, Axel ^{[1
]}

Sullivan, Kate ^{[2
]}

Jaeger, Emma ^{[1
]}

Fielding, Sarah ^{[2
]}

Rowan, Andrew ^{[1
]}

Vijayakrishnan, Jayaram ^{[2
]}

Domingo, Enric ^{[1
]}

Chandler, Ian ^{[2
]}

Kemp, Zoe ^{[1
]}

Qureshi, Mobshra ^{[2
]}

Farrington, Susan M. ^{[3
,4
]}

Tenesa, Albert ^{[3
,4
]}

Prendergast, James G. D. ^{[3
,4
]}

Barnetson, Rebecca A. ^{[3
,4
]}

Penegar, Steven ^{[2
]}

Barclay, Ella ^{[1
]}

Wood, Wendy ^{[2
]}

Martin, Lynn ^{[1
,4
,5
,6
]}

Gorman, Maggie ^{[1
]}

Thomas, Huw ^{[7
]}

Peto, Julian ^{[8
,9
]}

Bishop, D. Timothy ^{[10
]}

Gray, Richard ^{[11
]}

Maher, Eamonn R. ^{[5
,6
]}

Lucassen, Anneke ^{[12
,13
]}

Kerr, David ^{[14
]}

Evans, D. Gareth R. ^{[4
]}

Schafmayer, Clemens ^{[15
,16
]}

Buch, Stephan ^{[19
,20
]}

Voelzke, Henry ^{[17
,18
]}

Hampe, Jochen ^{[19
]}

Schreiber, Stefan ^{[16
,20
]}

John, Ulrich ^{[17
,18
]}

Koessler, Thibaud ^{[38
]}

Pharoah, Paul ^{[38
]}

van Wezel, Tom ^{[39
]}

Morreau, Hans ^{[39
]}

Wijnen, Juul T. ^{[21
]}

Hopper, John L. ^{[22
]}

Southey, Melissa C. ^{[23
]}

Giles, Graham G. ^{[24
]}

Severi, Gianluca ^{[24
]}

机构：

[1] London Res Inst, Mol & Populat Genet Lab, London WC2A 3PX, England

[2] Inst Canc Res, Sect Canc Genet, Sutton SM2 5NG, Surrey, England

[3] Western Gen Hosp, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland

[4] St Marys Hosp, Dept Med Genet, Manchester M13 0JH, Lancs, England

[5] Univ Birmingham, Sch Med, Dept Med & Mol Genet, Birmingham B15 2TG, W Midlands, England

[6] Birmingham Womens Hosp, W Midlands Reg Genet Serv, Birmingham B15 2TG, W Midlands, England

[7] St Marks Hosp, Family Canc Clin, Harrow HA1 3UJ, Middx, England

[8] Univ London London Sch Hyg & Trop Med, Noncommunicable Dis Epidemiol Unit, London WC1E 7HT, England

[9] Inst Canc Res, Canc Res UK Epidemiol & Genet Unit, Sutton SM2 5NG, Surrey, England

[10] Univ Leeds, Epidemiol & Biostat Sect, Leeds Inst Mol Med, Leeds LS9 7TF, W Yorkshire, England

[11] Univ Birmingham, Birmingham Clin Trials Unit, Birmingham B15 2TA, W Midlands, England

[12] Univ Southampton, Southampton SO16 5YA, Hants, England

[13] Princess Anne Hosp, Wessex Clib Genet Serv, Southampton SO16 5YA, Hants, England

[14] Univ Oxford, Radcliffe Infirm, Dept Clin Pharmacol, Oxford OX2 6HA, England

[15] Univ Hosp Schleswig Holstein, Dept Gen & Thorac Surg, D-24105 Kiel, Germany

[16] Univ Hosp Schleswig Holstein, POPGEN Biobank, D-24105 Kiel, Germany

[17] Ernst Moritz Arndt Univ Greifswald, Univ Hosp, SHIP Biobank, D-17487 Greifswald, Germany

[18] Ernst Moritz Arndt Univ Greifswald, Univ Hosp, Dept Community Med, D-17487 Greifswald, Germany

[19] Univ Hosp Schleswig Holstein, Dept Gen Internal Med, D-24105 Kiel, Germany

[20] Univ Hosp Schleswig Holstein, Inst Clin Mol Biol, D-24105 Kiel, Germany

[21] Leiden Univ, Med Ctr, Ctr Human & Clin Genet, NL-2333 ZA Leiden, Netherlands

[22] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic 3053, Australia

[23] Univ Melbourne, Genet Epidemiol Lab, Dept Pathol, Parkville, Vic 3052, Australia

[24] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic 3053, Australia

[25] IDIBAPS, Dept Gastroenterol, Inst Malalties Digest & Metab, Hosp Clin,CIBER EHD, Barcelona, Catalonia, Spain

[26] CeGen USC, CIBERER, Genom Med Grp, FPGMX,Spanish Natl Genotyping Ctr,Hosp Clin, Santiago De Compostela, Galicia, Spain

[27] DKFZ, Div Mol Genet Epidemiol, German Canc Res Ctr, D-69120 Heidelberg, Germany

[28] Karolinska Inst, Ctr Family & Community Med, S-14183 Huddinge, Sweden

[29] Acad Sci Czech Republic, Inst Expt Med, Prague 14200, Czech Republic

[30] Western Hosp, Dept Med Oncol & Clin Haematol, Footscray, Vic 3011, Australia

[31] Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China

[32] Univ Extremadura, Dept Pharmacol, Sch Med, Badajoz, Spain

[33] San Carlos Univ Hosp, Serv Gastroenterol, Madrid, Spain

[34] Hosp San Carlos, Mol Oncol Lab, Madrid 28040, Spain

[35] Univ Helsinki, Dept Med Genet, Genome Scale Biol Res Program, Helsinki, Finland

[36] London Res Inst, London WC2A 3PX, England

[37] Univ Edinburgh, Edinburgh EH8 9AG, Midlothian, Scotland

[38] Univ Cambridge, Can Res United Kingdom Dept Oncol, Strangeways Res Lab, Cambridge CB1 8RN, England

[39] Leiden Univ, Med Ctr, Dept Pathol, NL-2333 ZA Leiden, Netherlands

来源：

NATURE GENETICS | 2008年 / 40卷 / 05期

基金：

英国医学研究理事会;

关键词：

D O I：

10.1038/ng.111

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping ( 10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P=2.5 x 10(-13) overall; P=6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P=3.3 x 10(-18) overall; P=9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.

引用

页码：623 / 630

页数：8

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