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Original article
Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO and CCFR consortia
  1. Iona Cheng1,
  2. Jonathan M Kocarnik2,
  3. Logan Dumitrescu3,4,
  4. Noralane M Lindor5,
  5. Jenny Chang-Claude6,
  6. Christy L Avery7,
  7. Christian P Caberto8,
  8. Shelly-Ann Love7,
  9. Martha L Slattery9,
  10. Andrew T Chan10,11,
  11. John A Baron12,
  12. Lucia A Hindorff13,
  13. Sungshim Lani Park8,
  14. Fredrick R Schumacher14,
  15. Michael Hoffmeister15,
  16. Peter Kraft16,
  17. Anne M Butler7,
  18. David J Duggan17,
  19. Lifang Hou18,
  20. Chris S Carlson2,
  21. Kristine R Monroe14,
  22. Yi Lin2,
  23. Cara L Carty2,
  24. Sue Mann2,
  25. Jing Ma10,
  26. Edward L Giovannucci10,19,
  27. Charles S Fuchs10,20,
  28. Polly A Newcomb2,
  29. Mark A Jenkins21,
  30. John L Hopper21,
  31. Robert W Haile22,
  32. David V Conti14,
  33. Peter T Campbell23,
  34. John D Potter2,24,
  35. Bette J Caan25,
  36. Robert E Schoen26,
  37. Richard B Hayes27,
  38. Stephen J Chanock28,
  39. Sonja I Berndt28,
  40. Sebastien Küry29,
  41. Stephane Bézieau29,
  42. Jose Luis Ambite30,
  43. Gowri Kumaraguruparan30,
  44. Danielle M Richardson5,
  45. Robert J Goodloe4,
  46. Holli H Dilks4,31,
  47. Paxton Baker4,
  48. Brent W Zanke32,
  49. Mathieu Lemire33,
  50. Steven Gallinger34,35,
  51. Li Hsu2,36,
  52. Shuo Jiao2,
  53. Tabitha A Harrison2,
  54. Daniela Seminara37,
  55. Christopher A Haiman14,
  56. Charles Kooperberg2,
  57. Lynne R Wilkens8,
  58. Carolyn M Hutter2,38,
  59. Emily White2,38,
  60. Dana C Crawford3,4,
  61. Gerardo Heiss7,
  62. Thomas J Hudson33,39,40,
  63. Hermann Brenner15,41,
  64. William S Bush4,42,
  65. Graham Casey14,
  66. Loïc Le Marchand8,
  67. Ulrike Peters2,38
  1. 1Cancer Prevention Institute of California, Fremont, California, USA
  2. 2Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  3. 3Departments of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
  4. 4Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, USA
  5. 5Department of Health Science Research, Mayo Clinic Arizona, Arizona, USA
  6. 6Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
  7. 7Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
  8. 8Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii, USA
  9. 9Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
  10. 10Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard, Boston, Massachusetts, USA
  11. 11Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
  12. 12Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
  13. 13Office of Population Genomics, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
  14. 14Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  15. 15Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  16. 16Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
  17. 17Division of Genetic Basis of Human Disease, Translational Genomics Research Institute, Phoenix, Arizona, USA
  18. 18Department of Preventive Medicine, Northwestern University, Chicago, Illinois, USA
  19. 19Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA
  20. 20Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
  21. 21Centre for Molecular, Environmental, Genetic & Analytic Epidemiology, School of Population Health, The University of Melbourne, Melbourne, Australia
  22. 22Stanford Cancer Institute, Palo Alto, California, USA
  23. 23Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA
  24. 24Centre for Public Health Research, Massey University, Wellington, New Zealand
  25. 25Division of Research, Kaiser Permanente Medical Care Program, Oakland, California, USA
  26. 26Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pennsylvania, USA
  27. 27Division of Epidemiology, Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA
  28. 28Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
  29. 29Service de Génétique Médicale, CHU Nantes, Nantes, France
  30. 30Information Sciences Institute, University of Southern California, Marinadel Rey, California, USA
  31. 31Vanderbilt Technologies for Advanced Genomics, Vanderbilt University, Nashville, Tennessee, USA
  32. 32Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  33. 33Ontario Institute for Cancer Research, Toronto, Ontario, Canada
  34. 34Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada
  35. 35Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada
  36. 36Department of Biostatistics, University of Washington, Seattle, Washington, USA
  37. 37Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
  38. 38Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA
  39. 39Department Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  40. 40Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
  41. 41Germany German Cancer Consortium (DKTK), Heidelberg, Germany
  42. 42Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, USA
  1. Correspondence to Dr Iona Cheng, Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA 94538, USA; iona.cheng{at}cpic.org and Dr Jonathan Kocarnik, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, M4-B402, PO Box 19024, Seattle, WA 98109, USA; jkocarni{at}fhcrc.org

Abstract

Objective Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer.

Design We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10−4 was used to determine statistical significance of the associations.

Results Two correlated SNPs—rs10090154 and rs4242382—in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10−5), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites.

Conclusions This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.

  • COLORECTAL CANCER
  • EPIDEMIOLOGY
  • POLYMORPHIC VARIATION

https://doi.org/10.1136/gutjnl-2013-305189

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