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Carcinogenesis. 2015 Sep;36(9):999-1007. doi: 10.1093/carcin/bgv086. Epub 2015 Jun 12.

Identification of a common variant with potential pleiotropic effect on risk of inflammatory bowel disease and colorectal cancer.

Author information

1
Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA.
2
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
3
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany, German Cancer Cosortium (DKTK), Heidelberg, Germany.
4
Whitman College, Walla Walla, WA, USA.
5
Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA.
6
Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan.
7
Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
8
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
9
CHU Nantes, Service de Génétique Médicale, Nantes, France.
10
Division of Hematology, Faculty of Medicine, The University of Ottawa, Ottawa, ON, Canada.
11
Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
12
Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
13
Program in Molecular and Genetic Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
14
Keck School of Medicine, University of Southern California, Los Angles, CA, USA.
15
Systems Imagination, Computational Biology, Pheonix, AZ, USA.
16
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, Department of Epidemiology, Indiana University School of Public Health, Indianapolis, IN, USA.
17
Department of Surgery, University Health Network Toronto General Hospital, Toronto, ON, Canada.
18
Stanford Cancer Institute, Palo Alto, CA, USA.
19
Division of Epidemiology, New York University School of Medicine, New York, NY, USA.
20
Department of Epidemiology, Indiana University School of Public Health, Indianapolis, IN, USA.
21
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
22
Melbourne School of Population Health, The University of Melbourne, Melbourne, Australia.
23
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
24
Ontario Institute for Cancer Research, Toronto, ON, Canada.
25
Department of Health Science Services, Mayo Clinic, Scottsdale, AZ, USA.
26
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
27
Department of Pathology, The University of Tokyo Hospital, Tokyo, Japan.
28
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
29
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
30
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, Department of Epidemiology, University of Washington, Seattle, WA, USA, Center for Public Health Research, Massey University, Wellington, New Zealand.
31
Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
32
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
33
Department of Social and Preventive Medicine, University of Buffalo, Buffalo, NY, USA.
34
Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
35
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, USA.
36
Ontario Institute for Cancer Research, Toronto, ON, Canada, Department of Medical Biophysics, University of Toronto, Toronto, ON, USA.
37
Program in Molecular and Genetic Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA, Department of Epidemiology, Indiana University School of Public Health, Indianapolis, IN, USA.
38
Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA.
39
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA achan@mgh.harvard.edu shuji_ogino@dfci.harvard.edu.
40
Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA, Department of Epidemiology, Indiana University School of Public Health, Indianapolis, IN, USA, achan@mgh.harvard.edu shuji_ogino@dfci.harvard.edu.

Abstract

Although genome-wide association studies (GWAS) have separately identified many genetic susceptibility loci for ulcerative colitis (UC), Crohn's disease (CD) and colorectal cancer (CRC), there has been no large-scale examination for pleiotropy, or shared genetic susceptibility, for these conditions. We used logistic regression modeling to examine the associations of 181 UC and CD susceptibility variants previously identified by GWAS with risk of CRC using data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. We also examined associations of significant variants with clinical and molecular characteristics in a subset of the studies. Among 11794 CRC cases and 14190 controls, rs11676348, the susceptibility single nucleotide polymorphism (SNP) for UC, was significantly associated with reduced risk of CRC (P = 7E-05). The multivariate-adjusted odds ratio of CRC with each copy of the T allele was 0.93 (95% CI 0.89-0.96). The association of the SNP with risk of CRC differed according to mucinous histological features (P heterogeneity = 0.008). In addition, the (T) allele was associated with lower risk of tumors with Crohn's-like reaction but not tumors without such immune infiltrate (P heterogeneity = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (P heterogeneity = 0.03). The minor allele (T) in SNP rs11676348, located downstream from CXCR2 that has been implicated in CRC progression, is associated with a lower risk of CRC, particularly tumors with a mucinous component, Crohn's-like reaction and MSI-high. Our findings offer the promise of risk stratification of inflammatory bowel disease patients for complications such as CRC.

PMID:
26071399
PMCID:
PMC4573660
DOI:
10.1093/carcin/bgv086
[Indexed for MEDLINE]
Free PMC Article

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