Human Molecular Genetics Advance Access originally published online on August 27, 2008
Human Molecular Genetics 2008 17(23):3720-3727; doi:10.1093/hmg/ddn267
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Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer
1 Section of Cancer Genetics, Institute of Cancer Research, Sutton SM2 5NG, UK 2 Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX UK 3 Family Cancer Clinic, St Mark's Hospital, Watford Road, Harrow HA1 3UJ, UK 4 Non-Communicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, UK 5 Institute of Cancer Research, Surrey, UK 6 Cancer Research UK Epidemiology and Genetics Unit, Institute of Cancer Research, London, UK 7 Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK 8 Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK 9 Department of Medical and Molecular Genetics, University of Birmingham School of Medicine 10 West Midlands Regional Genetics Service, Birmingham Women's Hospital, Edgbaston, Birmingham, UK 11 University of Southampton and Wessex Clinical Genetics Service, Mailpoint 105, Princess Anne Hospital, Coxford Road, Southampton SO16 5YA, UK 12 Department of Clinical Pharmacology, Oxford University, Radcliffe Infirmary, Oxford OX2 6HA, UK 13 Department of Medical Genetics, St Mary's Hospital, Manchester M13 0JH, UK 14 Department of Pathology 15 Center for Human and Clinical Genetics, Leiden University Medical Center, Albinusdreef 2 2333ZA, Leiden, The Netherlands 16 Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, 723 Swanston street, Carlton VIC 3053, Australia 17 Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Grattan street, Parkville VIC 3052, Australia 18 Cancer Epidemiology Centre, The Cancer Council Victoria, 1 Rathdowne street, Carlton VIC 3053, Australia 19 Department of Gastroenterology, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedes Hepáticas y Digestivas (CIBER-EHD), IDIBAPS, Barcelona, Catalonia, Spain 20 Genomic Medicine Group, Fundacion Publica Galega de Medicina Xenomica (FPGMX), Spanish National Genotyping Center (CeGen)-University of Santiago Compostela, CIBERER, Hospital Clínico, Santiago de Compostela, Galicia, Spain 21 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580 D-69120, Heidelberg, Germany 22 Center for Family and Community Medicine, Karolinska Institute 141 83, Huddinge, Sweden 23 Institute of Experimental Medicine at the Academy of Sciences, Czech Rep., Videnska 1083 14200, Prague, Czech Republic 24 Department of Medical Oncology and Clinical Haematology, Western Hospital, Footscray 3011, Victoria, Australia 25 The University of Hong Kong, Hong Kong 26 Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain 27 Service of Gastroenterology, San Carlos University Hospital, Madrid, Spain 28 Molecular Oncology Laboratory, Hospital San Carlos 28040, Madrid, Spain 29 Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland 30 Bioinformatics and Biostatistics, London Research Institute, Cancer Research UK, London WC2A 3PX, UK
* To whom correspondence should be addressed at: Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK. Tel: +44 2087224175; Fax: +44 2087224365; Email: richard.houlston{at}icr.ac.uk
Received June 6, 2008; Revised July 24, 2008; Accepted August 24, 2008
The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case–control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12–1.22; P = 1.08 x 10–12) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (ORper allele = 1.19; 95% CI: 1.15–1.23; Ptrend = 7.4 x 10–24). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.
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