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A genome-wide association study on copy-number variation identifies a 11q11 loss as a candidate susceptibility variant for colorectal cancer |
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| Authors: | C. Fernandez-Rozadilla J. B. Cazier I. Tomlinson A. Brea-Fernández M. J. Lamas M. Baiget L. A. López-Fernández J. Clofent L. Bujanda D. Gonzalez L. de Castro K. Hemminki X. Bessa M. Andreu R. Jover R. Xicola X. Llor V. Moreno A. Castells S. Castellví-Bel A. Carracedo C. Ruiz-Ponte |
| Affiliation: | 1. Fundación Pública Galega de Medicina Xenómica (FPGMX)-SERGAS, Grupo de Medicina Xenómica, IDIS, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERer), Complexo Hospitalario Universitario de Santiago, Choupana s/n, 15706, Santiago, Spain 2. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK 3. Bioinformatics Core Group, Department of Oncology, University of Oxford, Oxford, UK 4. NIHR Comprehensive Biomedical Research Centre, University of Oxford, Oxford, OX3 7BN, UK 5. Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERer)-Universidad de Santiago de Compostela, 15706, Santiago, Spain 6. Oncology Pharmacy Unit, Complejo Hospitalario Universitario of Santiago (CHUS), 15706, Santiago, Spain 7. Genetics Department, Hospital de Santa Creu I Sant Pau, 08025, Barcelona, Spain 8. Pharmacogenetics and Pharmacogenomics Laboratory, Servicio de Farmacia, Instituto de Investigación Sanitaria Gregorio Mara?ón, Hospital General Universitario Gregorio Mara?ón, 28007, Madrid, Spain 10. Section of Digestive Diseases, Internal Medicine Department, Hospital Sagunto, 46520, Valencia, Spain 9. Gastroenterology Department, Hospital do Meixoeiro, 36214, Vigo, Spain 11. Colorectal Cancer Multidisciplinary Unit, Donostia Hospital, University of the Basque Country, San Sebastián, Spain 12. Servicio de Patologia Digestiva, Hospital Sant PAu, Barcelona, 08003, Spain 14. Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany 15. Center for Primary Health Care Research, Lund University, Malm?, Sweden 16. Gastroenterology Department, Hospital del Mar, Barcelona, Spain 17. Gastroenterology Department, Hospital General de Alicante, Alicante, Spain 18. Section of Digestive Diseases and Nutrition, University of Illinois at Chicago, Chicago, IL, USA 19. Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Centre (IDIBELL), CIBERESP, Barcelona, 08907, Spain 20. Department of Gastroenterology, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain 21. Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jidda, Saudi Arabia |
| Abstract: | Colorectal cancer (CRC) is a complex disease, and therefore its development is determined by the combination of both environmental factors and genetic variants. Although genome-wide association studies (GWAS) of SNP variation have conveniently identified 20 genetic variants so far, a significant proportion of the observed heritability is yet to be explained. Common copy-number variants (CNVs) are one of the most important genomic sources of variability, and hence a potential source to explain part of this missing genetic fraction. Therefore, we have performed a GWAS on CNVs to explore the relationship between common structural variation and CRC development. Phase 1 of the GWAS consisted of 881 cases and 667 controls from a Spanish cohort. Copy-number status was validated by quantitative PCR for each of those common CNVs potentially associated with CRC in phase I. Subsequently, SNPs were chosen as proxies for the validated CNVs for phase II replication (1,342 Spanish cases and 1,874 Spanish controls). Four common CNVs were found to be associated with CRC and were further replicated in Phase II. Finally, we found that SNP rs1944682, tagging a 11q11 CNV, was nominally associated with CRC susceptibility (p value = 0.039; OR = 1.122). This locus has been previously related to extreme obesity phenotypes, which could suggest a relationship between body weight and CRC susceptibility. |
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