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Hum Genet. 2015 Nov;134(11-12):1249-1262. doi: 10.1007/s00439-015-1598-6. Epub 2015 Sep 24.

A genome-wide association study for colorectal cancer identifies a risk locus in 14q23.1.

Author information

1
Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
2
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
3
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
4
Occupational and Environmental Epidemiology Branch, National Cancer Institute, Bethesda, MD, USA.
5
Service de Génétique Médicale, CHU Nantes, Nantes, France.
6
EA 4273, Faculté de médecine, Université de Nantes, Nantes, France.
7
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
8
German Cancer Consortium (DKTK), Heidelberg, Germany.
9
Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
10
American Cancer Society, Atlanta, GA, USA.
11
Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
12
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
13
Division of Cancer Epidemiology, Unit of Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
14
USC Norris Comprehensive Cancer Center, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
15
Samuel Lunenfeld Research Institute, Toronto, ON M5S 1X5, Canada.
16
Division of General Surgery, Toronto General Hospital, Toronto, ON M5G 2C4, Canada.
17
Department of Medicine, Division of Oncology, Stanford University, California, USA.
18
Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
19
Department of Preventive Medicine and the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Illinois.
20
Department of Biostatistics, University of Washington, Seattle, Washington.
21
Case Comprehensive Cancer Center and Swetland Center for Environmental Health, Case Western Reserve University, Cleveland, Ohio.
22
Department of Health Sciences Research, Mayo Clinic, Scottsdale, Arizona.
23
Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington.
24
Centre for Public Health Research, Massey University, Wellington, New Zealand.
25
Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel.
26
Clalit Health Services National Cancer Control Center, Haifa, Israel.
27
Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
28
Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
29
Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA.
30
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
31
Human Genetics Foundation (HuGeF), Torino, Italy.
32
Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA.
33
Discipline of Genetics, Memorial University of Newfoundland, St. John's, NF A1B 3V6, Canada.
34
Cancer Care Ontario, University of Toronto, Toronto, Ontario, Canada.
35
USC Norris Comprehensive Cancer Center, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
36
School of Public Health, University of Washington, Seattle, Washington.
37
Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A1, Canada.
38
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada.
#
Contributed equally

Abstract

Over 50 loci associated with colorectal cancer (CRC) have been uncovered by genome-wide association studies (GWAS). Identifying additional loci has the potential to help elucidate aspects of the underlying biological processes leading to better understanding of the pathogenesis of the disease. We re-evaluated a GWAS by excluding controls that have family history of CRC or personal history of colorectal polyps, as we hypothesized that their inclusion reduces power to detect associations. This is supported empirically and through simulations. Two-phase GWAS analysis was performed in a total of 16,517 cases and 14,487 controls. We identified rs17094983, a SNP associated with risk of CRC [p = 2.5 × 10(-10); odds ratio estimated by re-including all controls (OR) = 0.87, 95% confidence interval (CI) 0.83-0.91; minor allele frequency (MAF) = 13%]. Results were replicated in samples of African descent (1894 cases and 4703 controls; p = 0.01; OR = 0.86, 95% CI 0.77-0.97; MAF = 16 %). Gene expression data in 195 colon adenocarcinomas and 59 normal colon tissues from two different studies revealed that this locus has genotypes that are associated with RTN1 (Reticulon 1) expression (p = 0.001), a protein-coding gene involved in survival and proliferation of cancer cells which is highly expressed in normal colon tissues but has significantly reduced expression in tumor cells (p = 1.3 × 10(-8)).

PMID:
26404086
PMCID:
PMC4687971
DOI:
10.1007/s00439-015-1598-6
[Indexed for MEDLINE]
Free PMC Article

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