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Original Article
Genome-wide association study identified copy number variants associated with sporadic colorectal cancer risk
  1. Lai Fun Thean1,
  2. Yee Syuen Low1,
  3. Michelle Lo1,
  4. Yik-Ying Teo2,
  5. Woon-Puay Koh2,3,
  6. Jian-Min Yuan4,5,
  7. Min Hoe Chew1,
  8. Choong Leong Tang1,
  9. Peh Yean Cheah1,2,3
  1. 1 Department of Colorectal Surgery, Singapore General Hospital, Singapore, Singapore
  2. 2 Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
  3. 3 Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
  4. 4 Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  5. 5 Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA
  1. Correspondence to Dr Peh Yean Cheah, Department of Colorectal Surgery, Singapore General Hospital, Academia, 20 College Road, Discovery Tower, Level 9, Singapore 169856, Singapore; cheah.peh.yean{at}


Background Multiple single nucleotide polymorphisms (SNPs) have been associated with colorectal cancer (CRC) risk. The role of structural or copy number variants (CNV) in CRC, however, remained unclear. We investigated the role of CNVs in patients with sporadic CRC.

Methods A genome-wide association study (GWAS) was performed on 1000 Singapore Chinese patients aged 50 years or more with no family history of CRC and 1000 ethnicity-matched, age-matched and gender-matched healthy controls using the Affymetrix SNP 6 platform. After 16 principal component corrections, univariate and multivariate segmentations followed by association testing were performed on 1830 samples that passed quality assurance tests.

Results A rare CNV region (CNVR) at chromosome 14q11 (OR=1.92 (95% CI 1.59 to 2.32), p=2.7e-12) encompassing CHD8, and common CNVR at chromosomes 3q13.12 (OR=1.54 (95% CI 1.33 to 1.77), p=2.9e-9) and 12p12.3 (OR=1.69 (95% CI 1.41 to 2.01), p=2.8e-9) encompassing CD47 and RERG/ARHGDIB, respectively, were significantly associated with CRC risk. CNV loci were validated in an independent replication panel using an optimised copy number assay. Whole-genome expression data in matched tumours of a subset of cases demonstrated that copy number loss at CHD8 was significantly associated with dysregulation of several genes that perturb the Wnt, TP53 and inflammatory pathways.

Conclusions A rare CNVR at 14q11 encompassing the chromatin modifier CHD8 was significantly associated with sporadic CRC risk. Copy number loss at CHD8 altered expressions of genes implicated in colorectal tumourigenesis.

  • copy numbervariant
  • colorectal cancer risk
  • genome-wide association study
  • chromatin remodeler chd8
  • rerg/arhgdib

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  • Contributors Study concept and design: PYC; acquisition of data: LFT, YSL and ML; analysis and interpretation of data: LFT, YSL, Y-YT and PYC; drafting of the manuscript: PYC; critical revision of the manuscript: PYC; obtained funding: PYC; administrative, technical or material support: W-PK, J-MY, CLT and MHC; study supervision: PYC.

  • Funding This work was supported by funding from the National Medical Research Council of Singapore (NMRC/1193/2008 and NMRC/OFIRG/0004/2016) to PYC. The Singapore Chinese Health Study was supported by the National Institutes of Health, USA (grant numbers: R01 CA144034 and UMI CA182876).

  • Competing interests None declared.

  • Ethics approval Collection of samples and clinicopathological data from patients and healthy controls was undertaken with written informed consent and approval from SingHealth Centralized Institutional Review Board B. The conduct of the Singapore Chinese Health Study was approved by the Institutional Review Boards of the National University of Singapore.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The CNVRs at chromosomes 3, 12 and 14 were submitted to the ClinVar database () under submission numbers SUB1733257, SUB1734044 and SUB1734047, respectively.