We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10 -10), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10 -10) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10 -10) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.
Bibliographical noteFunding Information:
For the Helsinki study, the work was supported by grants from the Academy of Finland (Finnish Centre of Excellence Program; 20062011), the Finnish Cancer Society and the Sigrid Juselius Foundation. This work of the Colon Cancer Family Registry (CFR) was supported by the US National Cancer Institute, National Institutes of Health (CA95011), and through cooperative agreements with members of the Colon CFR and Principal Investigators. Collaborating centers include the Australasian Colorectal Cancer Family Registry (U01 CA097735), the Familial Colorectal Neoplasia Collaborative Group (U01 CA074799), the 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 US National Cancer Institute, National Institutes of Health (U01CA122839 to G.C.).
Cancer Research UK provided principal funding for this study individually to R.S.H. (C1298/A8362–Bobby Moore Fund for Cancer Research UK), I.P.T. and M.G.D. At the Institute of Cancer Research, additional funding was provided by a Centre Grant from Core as part of the Digestive Cancer Campaign, the National Cancer Research Network and the NHS via the Biological Research Centre of the NIHR at the Royal Marsden Hospital NHS Trust. S.L. received a PhD studentship from Cancer Research UK, I.C. received a Clinical Research Training Fellowship from St. George’s Hospital Medical School, and N.W. received a PhD Studentship from the Institute of Cancer Research. M.H. was in receipt of a PostDoctoral Training post from the Leukaemia Lymphoma Research Fund. In Oxford, additional funding was provided by the Oxford Comprehensive Biomedical Research Centre (E.D., C.P. and I.P.T.) and the European Union Framework Programme 7 (FP7) CHIBCHA grant (A.M.J., L.G.C.C. and I.P.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 the 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). In Edinburgh, funding was provided by a Cancer Research UK Programme Grant (C348/A12076) and a Centre Grant from the CORE Charity. E.T. was funded by a Cancer Research UK Fellowship (C31250/A10107). L.Y.O. is supported by a Cancer Research UK Research Training Fellowship (C10195/A12996). C. Smillie is supported by an MRC Research Studentship to the MRC Human Genetics Unit (HGU). We gratefully acknowledge the work of M. Walker and S. Reid in technical support, R. Wilson (SOCCS3 and COGS study coordinator), G. Barr for data entry in SOCCS studies, the research nurse recruitment teams, the Wellcome Trust Clinical Research Facility for sample preparation and all surgeons, oncologists and pathologists throughout Scotland at contributing centers. Lothian Birth Cohort Illumina genotyping was supported by the UK Biotechnology and Biological Sciences Research Council (BBSRC). Phenotype collection in the Lothian Birth Cohort 1921 was supported by the BBSRC, The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research into Ageing (continues as part of Age UK’s The Disconnected Mind project). The work on the Lothian Birth Cohorts was undertaken at the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the crosscouncil Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged. For the Cambridge study, we thank the SEARCH study team and all the participants in the study. SEARCH is funded by a grant from Cancer Research UK (C490/A10124). In Cardiff, the work was supported by the Kidani Trust, Tenovus, Cancer Research Wales, The Bobby Moore Fund from CRUK (C10314/A4886), the Wales Assembly Government NISCHR Cancer Genetics BRU and the Wales Gene Park (all to J.P.C.). We acknowledge the use of DNA from the blood samples collected from COIN and COINB funded by Cancer Research UK and the MRC. We also acknowledge the use of DNA from the NBS (UKBS) collection, funded by the Wellcome Trust (076113/C/04/Z), by the Juvenile Diabetes Research Foundation (WT061858) and by the NIHR of England. The COINB Collaborative Group includes H. Wasan, T. Maughan, R. Adams, R. Wilson, A. Madi, E. Hodgkinson, M. Pope, P. Rogers and J. Cassidy. Research was also funded by the European Union FP7 (FP7/2072013) under grant 258236, FP7 collaborative project SYSCOL. The Swedish sample and data resource were 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 LowRisk Colorectal Cancer Study Group.
The Japanese study was conducted as part of the BioBank Japan Project that was supported by the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government.