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Gastroenterology. 2016 Jun;150(7):1633-1645. doi: 10.1053/j.gastro.2016.02.076. Epub 2016 Mar 8.

Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk.

Author information

1
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
2
Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
3
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
4
State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
5
Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea; Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, South Korea.
6
Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
7
Molecular Epidemiology Branch, National Cancer Center, Goyang-si, South Korea; Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
8
Institute for Health Promotion, Department of Epidemiology and Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, South Korea.
9
Department of Social and Preventive Medicine, Hallym University College of Medicine, Okcheon-dong, South Korea.
10
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee; General Department, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
11
RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
12
Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea.
13
Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
14
Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
15
Center for Colorectal Cancer, National Cancer Center, Goyang-si, South Korea.
16
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
17
School of Public Health, Sun Yat-sen University, Guangzhou, China.
18
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee.
19
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
20
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
21
Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
22
CHU Nantes, Service de Génétique Médicale, Nantes, France.
23
USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
24
Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
25
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
26
Department of Surgery, Chonnam National University Medical School, Gwangju, South Korea.
27
Center for Colorectal Cancer, National Cancer Center, Goyang-si, South Korea; Department of Surgery, Seoul National University Hospital, Seoul, South Korea.
28
Department of Public Health and Occupational Medicine, Mie University Graduate School of Medicine, Mie, Japan.
29
Department of Hemato-oncology, Chonnam National University Medical School, Gwangju, South Korea.
30
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee. Electronic address: wei.zheng@vanderbilt.edu.

Abstract

BACKGROUND & AIMS:

Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC.

METHODS:

This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases.

RESULTS:

We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10(-8) to 1.24 × 10(-12): 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P < .05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2.

CONCLUSIONS:

We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.

KEYWORDS:

Colon Cancer; Epidemiology; Single Nucleotide Polymorphisms; eQTL

PMID:
26965516
PMCID:
PMC4909543
DOI:
10.1053/j.gastro.2016.02.076
[Indexed for MEDLINE]
Free PMC Article

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