Whiffin, N., Hosking, F. J., Farrington, S. M., Palles, C., Dobbins, S. E., Zgaga, L., Lloyd, A., Kinnersley, B., Gorman, M., Tenesa, A., Broderick, P., Wang, Y. F., Barclay, E., Hayward, C., Martin, L., Buchanan, D. D., Win, A. K., Hopper, J., Jenkins, M., Lindor, N. M., Newcomb, P. A., Gallinger, S., Conti, D., Schumacher, F., Casey, G., Liu, T., Campbell, H., Lindblom, A., Houlston, R. S., Tomlinson, I. P., Dunlop, M. G., Swedish Low-Risk Colorectal, Canc (2014) Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis. HUMAN MOLECULAR GENETICS, 23 (17). pp. 4729-4737. ISSN 0964-6906

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Abstract

To identify common variants influencing colorectal cancer (CRC) risk, we performed a meta-analysis of five genome-wide association studies, comprising 5626 cases and 7817 controls of European descent. We conducted replication of top ranked single nucleotide polymorphisms (SNPs) in additional series totalling 14 037 cases and 15 937 controls, identifying a new CRC risk locus at 10q24.2 [rs1035209; odds ratio (OR) = 1.13, P = 4.54 x 10(-11)]. We also performed meta-analysis of our studies, with previously published data, of several recently purported CRC risk loci. We failed to find convincing evidence for a previously reported genome-wide association at rs11903757 (2q32.3). Of the three additional loci for which evidence of an association in Europeans has been previously described we failed to show an association between rs59336 (12q24.21) and CRC risk. However, for the other two SNPs, our analyses demonstrated new, formally significant associations with CRC. These are rs3217810 intronic in CCND2 (12p13.32; OR = 1.19, P = 2.16 x 10(-10)) and rs10911251 near LAMC1 (1q25.3; OR = 1.09, P = 1.75 x 10(-8)). Additionally, we found some evidence to support a relationship between, rs647161, rs2423297 and rs10774214 and CRC risk originally identified in East Asians in our European datasets. Our findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC.

Item Type:	Article
Authors (ICR Faculty only):	Houlston, Richard
All Authors:	Whiffin, N., Hosking, F. J., Farrington, S. M., Palles, C., Dobbins, S. E., Zgaga, L., Lloyd, A., Kinnersley, B., Gorman, M., Tenesa, A., Broderick, P., Wang, Y. F., Barclay, E., Hayward, C., Martin, L., Buchanan, D. D., Win, A. K., Hopper, J., Jenkins, M., Lindor, N. M., Newcomb, P. A., Gallinger, S., Conti, D., Schumacher, F., Casey, G., Liu, T., Campbell, H., Lindblom, A., Houlston, R. S., Tomlinson, I. P., Dunlop, M. G., Swedish Low-Risk Colorectal, Canc
Additional Information:	ISI Document Delivery No.: AM9YU Times Cited: 0 Cited Reference Count: 42 Whiffin, Nicola Hosking, Fay J. Farrington, Susan M. Palles, Claire Dobbins, Sara E. Zgaga, Lina Lloyd, Amy Kinnersley, Ben Gorman, Maggie Tenesa, Albert Broderick, Peter Wang, Yufei Barclay, Ella Hayward, Caroline Martin, Lynn Buchanan, Daniel D. Win, Aung Ko Hopper, John Jenkins, Mark Lindor, Noralane M. Newcomb, Polly A. Gallinger, Steve Conti, David Schumacher, Fred Casey, Graham Liu, Tao Campbell, Harry Lindblom, Annika Houlston, Richard S. Tomlinson, Ian P. Dunlop, Malcolm G. Cancer Research UK [C1298/A8362, C348/A12076]; European Union [258236]; FP7 collaborative project SYSCOL; COST Action [BM1206]; National Cancer Research Network; NHS via the Biological Research Centre of the National Institute for Health Research at the Royal Marsden Hospital NHS Trust; ICR; Sir John Fisher Foundation; Scottish Government Health Department, Chief Scientist Office [CZD/16/6]; UK Medical Research Council; Oxford Comprehensive Biomedical Research Centre; EU FP7 CHIBCHA grant; Wellcome Trust Centre for Human Genetics, Oxford [090532/Z/09/Z]; Swedish Cancer Society; Swedish Scientific Research Council; Stockholm Cancer Foundation; National Cancer Institute, National Institutes of Health under RFA [CA-95-011]; National Cancer Institute, National Institutes of Health [U01CA122839] Cancer Research UK provided principal funding for this study to R.S.H., I.P.M.T. and M.G.D. In addition, this work was supported by the European Union (FP7/207-2013) under grant 258236, FP7 collaborative project SYSCOL and COST Action BM1206.At the Institute of Cancer Research, the work was supported by a Programme Grant from Cancer Research UK (C1298/A8362-Bobby Moore Fund for Cancer Research UK). Additional support was provided by the National Cancer Research Network and the NHS via the Biological Research Centre of the National Institute for Health Research at the Royal Marsden Hospital NHS Trust. N.W. and B.K. were in receipt of PhD studentships from the ICR. B.K. additionally receives funding from the Sir John Fisher Foundation.In Edinburgh the work was supported by Programme Grant funding from Cancer Research UK (C348/A12076). We are most grateful to all participants of the SOCCS/COGS studies and Generation Scotland, without whom our research could not be conducted. We acknowledge the excellent technical support from CCGG technicians and the COGS/SOCCS operational team: study coordinators, recruitment nurses, data entry and collation. Generation Scotland is a collaboration between the University Medical Schools and NHS in Aberdeen, Dundee, Edinburgh and Glasgow. The Generation Scotland Family Health Study (http://www.generationscotland.org) was funded by a grant from the Scottish Government Health Department, Chief Scientist Office, CZD/16/6. Genotyping was funded by the UK Medical Research Council. We are grateful to GPs and Scottish School of Primary Care for help with recruitment to GS:SFHS. We acknowledge the excellent work of the whole GS team: academic researchers, clinic staff, laboratory technicians, clerical workers, statisticians and research managers. We acknowledge the expert support on sample preparation and genotyping by the Genetics Core of the Edinburgh University Wellcome Trust Clinical Research Facility.In Oxford additional funding was provided by the Oxford Comprehensive Biomedical Research Centre (C.P. and I.P.M.T.) and the EU FP7 CHIBCHA grant (I.P. M.T.). Core infrastructure support to the Wellcome Trust Centre for Human Genetics, Oxford was provided by grant (090532/Z/09/Z). We are grateful to many colleagues within UK Clinical Genetics Departments (for CORGI) and to many collaborators who participated in the VICTOR and QUASAR2 trials. We also thank colleagues from the UK National Cancer Research Network (for NSCCG).The Swedish sample and data resource was funded by the Swedish Cancer Society, the Swedish Scientific Research Council and the Stockholm Cancer Foundation. We acknowledge the contribution to recruitment and data collection of the Swedish Low-Risk Colorectal Cancer Study Group.The work of the Colon Cancer Family Registry CFR was supported by the National Cancer Institute, National Institutes of Health under RFA #CA-95-011 and through cooperative agreements with members of the Colon CFR and Principal Investigators. Collaborating centres include the Australasian Colorectal Cancer Family Registry (U01 CA097735), the USC Familial Colorectal Neoplasia Collaborative Group (U01 CA074799), Mayo Clinic Cooperative Familial Registry for Colon Cancer Studies (U01 CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783) and the Seattle Colorectal Cancer Family Registry (U01 CA074794). The Colon CFR GWAS was supported by funding from the National Cancer Institute, National Institutes of Health (U01CA122839 to GC). Oxford univ press Oxford
Uncontrolled Keywords:	colon-cancer gene-expression microsatellite instability chromatin states laminin isoforms cell-lines risk association metastasis annotation
Research teams:	ICR divisions > Genetics and Epidemiology > Molecular & Population Genetics ICR divisions > Molecular Pathology > Molecular & Population Genetics
Depositing User:	Alexander Smithson
Date Deposited:	04 Sep 2014 14:55
Last Modified:	04 Sep 2014 14:55
URI:	http://publications.icr.ac.uk/id/eprint/13515

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