Gastroenterology

Gastroenterology

Volume 150, Issue 7, June 2016, Pages 1633-1645
Gastroenterology

Original Research
Full Report: Basic and Translational—Alimentary Tract
Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk

https://doi.org/10.1053/j.gastro.2016.02.076Get rights and content

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.

Section snippets

Study Population

This study was conducted as part of the Asia Colorectal Cancer Consortium, including a total of 19,071 cases and 34,624 controls of East-Asian ancestry from 14 studies conducted in China, South Korea, and Japan (Supplementary Table 1). The details of these studies are described in the Supplementary Materials. Compared with our previous GWAS studies,8, 11 we expanded the discovery effort by including the Japan Biobank (BBJ) study (2814 cases/11,358 controls) and 3 additional studies (3519

Results

Combined analyses of data from the discovery and replication stages revealed 7 SNPs associated with CRC risk at the genome-wide significance level (P < 5 × 10−8), including rs4711689 at 6p21.1 (transcription factor EB [TFEB]), rs4919687 at 10q24.3 (cytochrome P450, family 17, subfamily A, polypeptide 1 [CYP17A1]), rs11064437 at 12p13.3 (SPSB2), rs2450115 and rs6469656 at 8q23.3 (eukaryotic translation initiation factor 3, subunit H [EIF3H]), rs10506868 at 10q25.2 (vesicle transport through

Discussion

In this multiple-staged GWAS with a total of 19,071 cases and 34,624 controls, we identified 4 novel risk loci for CRC (6p21.1, 8q23.3, 10q24.3, and 12p13.3) and new variants in 2 previously GWAS-identified loci (10q25.2 and 20q13.3). Using gene expression data from 188 CRC patients of East-Asian ancestry, we identified potential candidate genes, including TFEB, EIF3H, SPSB2, and RPS21.

At 12p13.3, rs11064437 lies at a splice receptor site within intron 1 of SPSB2. The T allele of rs11064437

Acknowledgments

The authors thank all study participants and research staff of all parent studies for their contributions and commitment to this project. The authors thank Vanderbilt staff members Jing He for data processing and analyses and Kimberly Kreth for editing and preparing the manuscript. The authors thank Dr Bing Zhang, Vanderbilt University for his suggestions on protein validation. Sample preparation and genotyping assays at Vanderbilt University were conducted at the Survey and Biospecimen Shared

References (59)

  • M. Lemire et al.

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

    Hum Genet

    (2015)
  • F.R. Schumacher et al.

    Genome-wide association study of colorectal cancer identifies six new susceptibility loci

    Nat Commun

    (2015)
  • N.A. Al-Tassan et al.

    A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer

    Sci Rep

    (2015)
  • H. Wang et al.

    Trans-ethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A

    Nat Commun

    (2014)
  • B. Zhang et al.

    Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk

    Nat Genet

    (2014)
  • N. Whiffin et al.

    Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis

    Hum Mol Genet

    (2014)
  • W.H. Jia et al.

    Genome-wide association analyses in East Asians identify new susceptibility loci for colorectal cancer

    Nat Genet

    (2013)
  • M.G. Dunlop et al.

    Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

    Nat Genet

    (2012)
  • R.S. Houlston et al.

    Meta-analysis of 3 genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33

    Nat Genet

    (2010)
  • I.P.M. Tomlinson et al.

    A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3

    Nat Genet

    (2008)
  • E. Jaeger et al.

    Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk

    Nat Genet

    (2008)
  • R.S. Houlston et al.

    Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer

    Nat Genet

    (2008)
  • A. Tenesa et al.

    Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21

    Nat Genet

    (2008)
  • I. Tomlinson et al.

    A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21

    Nat Genet

    (2007)
  • P. Broderick et al.

    A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk

    Nat Genet

    (2007)
  • B.W. Zanke et al.

    Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24

    Nat Genet

    (2007)
  • I.P. Tomlinson et al.

    Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer

    PLoS Genet

    (2011)
  • U. Peters et al.

    Genetic architecture of colorectal cancer

    Gut

    (2015)
  • Y. Li et al.

    MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes

    Genet Epidemiol

    (2010)
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    Conflicts of interest The authors disclose no conflicts.

    Funding The work at the Vanderbilt University School of Medicine was supported by US National Institutes of Health grants R01CA188214, R37CA070867, R01CA124558, P50CA095103, and R01CA148667, as well as Ingram Professorship and Anne Potter Wilson Chair funds from the Vanderbilt University School of Medicine. The Survey and Biospecimen Shared Resources and Vanderbilt Microarray Shared Resource are supported in part by the Vanderbilt-Ingram Cancer Center (P30CA068485). Studies (grant support) participating in the Asia Colorectal Cancer Consortium include the Shanghai Women's Health Study (US NIH, R37CA070867, UM1CA182910), Shanghai Men's Health Study (US NIH, R01CA082729, UM1CA173640), Shanghai Breast and Endometrial Cancer Studies (US NIH, R01CA064277 and R01CA092585; contributing only controls), Shanghai Colorectal Cancer Study 3 (US NIH, R37CA070867, R01CA188214 and Ingram Professorship funds), Guangzhou Colorectal Cancer Study (National Key Scientific and Technological Project, 2011ZX09307-001-04; National Basic Research Program, 2011CB504303, contributing only controls; Natural Science Foundation of China, 81072383, contributing only controls), Japan BioBank Colorectal Cancer Study (grant from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government), Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (HCES-CRC; grants from Chonnam National University Hwasun Hospital, HCRI15011-1). The Aichi Colorectal Cancer Study (Grant-in-Aid for Cancer Research, grant for the Third Term Comprehensive Control Research for Cancer and Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology, 17015018 and 221S0001), Korea-NCC (National Cancer Center) Colorectal Cancer Study (Basic Science Research Program through the National Research Foundation of Korea, 2010-0010276 and 2013R1A1A2A10008260; National Cancer Center Korea, 0910220), and the KCPS-II Colorectal Cancer Study (National R&D Program for Cancer Control, 1220180; Seoul R&D Program, 10526).

    Participating studies (grant support) in the GECCO, CORECT, and CCFR GWAS meta-analysis are GECCO (US NIH, U01CA137088 and R01CA059045), DALS (US NIH, R01CA048998), DACHS (German Federal Ministry of Education and Research, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, 01KH0404 and 01ER0814), HPFS (P01 CA 055075, UM1 CA167552, R01 CA137178, R01 CA151993 and P50 CA127003), NHS (UM1 CA186107, R01 CA137178, P01 CA87969, R01 CA151993 and P50 CA127003), OFCCR (US NIH, U01CA074783), PMH (US NIH, R01CA076366), PHS (US NIH, R01CA042182), VITAL (US NIH, K05CA154337), WHI (US NIH, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C), and PLCO (US NIH, Z01CP 010200, U01HG004446 and U01HG 004438). CORECT is supported by the National Cancer Institute as part of the GAME-ON consortium (US NIH, U19CA148107) with additional support from National Cancer Institute grants (R01CA81488 and P30CA014089), the National Human Genome Research Institute at the US NIH (T32HG000040) and the National Institute of Environmental Health Sciences at the US NIH (T32ES013678). CCFR is supported by the National Cancer Institute, US NIH under RFA CA-95-011 and through cooperative agreements with members of the Colon Cancer Family Registry and principal investigators of the Australasian Colorectal Cancer Family Registry (US NIH, U01CA097735), Familial Colorectal Neoplasia Collaborative Group (US NIH, U01CA074799) (University of Southern California), the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (US NIH, U01CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (US NIH, U01CA074783), Seattle Colorectal Cancer Family Registry (US NIH, U01CA074794). and the University of Hawaii Colorectal Cancer Family Registry (US NIH, U01CA074806). The GWAS work was supported by a National Cancer Institute grant (US NIH, U01CA122839). OFCCR was supported by a GL2 grant from the Ontario Research Fund, Canadian Institutes of Health Research and a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. T.J. Hudson and B.W. Zanke are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through support from the Ontario Ministry of Economic Development and Innovation. ASTERISK was funded by a Regional Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte Contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). PLCO data sets were accessed with approval through dbGaP (CGEMS prostate cancer scan, phs000207.v1.p1 (Yeager, M et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007;39:645–649); CGEMS pancreatic cancer scan, phs000206.v4.p3 (Amundadottir, L et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet 2009;41:986–990, and Petersen, GM et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet 2010;42:224–228); and GWAS of Lung Cancer and Smoking, phs000093.v2.p2 (Landi MT, et al. A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet 2009;85:679–691), which was funded by Z01CP 010200, U01HG004446 and U01HG 004438 from the US NIH).

    Author names in bold designate shared co-first authorship.

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