BMC Cancer (May 2020)

Knowledge-based analyses reveal new candidate genes associated with risk of hepatitis B virus related hepatocellular carcinoma

  • Deke Jiang,
  • Jiaen Deng,
  • Changzheng Dong,
  • Xiaopin Ma,
  • Qianyi Xiao,
  • Bin Zhou,
  • Chou Yang,
  • Lin Wei,
  • Carly Conran,
  • S. Lilly Zheng,
  • Irene Oi-lin Ng,
  • Long Yu,
  • Jianfeng Xu,
  • Pak C. Sham,
  • Xiaolong Qi,
  • Jinlin Hou,
  • Yuan Ji,
  • Guangwen Cao,
  • Miaoxin Li

DOI
https://doi.org/10.1186/s12885-020-06842-0
Journal volume & issue
Vol. 20, no. 1
pp. 1 – 10

Abstract

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Abstract Background Recent genome-wide association studies (GWASs) have suggested several susceptibility loci of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) by statistical analysis at individual single-nucleotide polymorphisms (SNPs). However, these loci only explain a small fraction of HBV-related HCC heritability. In the present study, we aimed to identify additional susceptibility loci of HBV-related HCC using advanced knowledge-based analysis. Methods We performed knowledge-based analysis (including gene- and gene-set-based association tests) on variant-level association p-values from two existing GWASs of HBV-related HCC. Five different types of gene-sets were collected for the association analysis. A number of SNPs within the gene prioritized by the knowledge-based association tests were selected to replicate genetic associations in an independent sample of 965 cases and 923 controls. Results The gene-based association analysis detected four genes significantly or suggestively associated with HBV-related HCC risk: SLC39A8, GOLGA8M, SMIM31, and WHAMMP2. The gene-set-based association analysis prioritized two promising gene sets for HCC, cell cycle G1/S transition and NOTCH1 intracellular domain regulates transcription. Within the gene sets, three promising candidate genes (CDC45, NCOR1 and KAT2A) were further prioritized for HCC. Among genes of liver-specific expression, multiple genes previously implicated in HCC were also highlighted. However, probably due to small sample size, none of the genes prioritized by the knowledge-based association analyses were successfully replicated by variant-level association test in the independent sample. Conclusions This comprehensive knowledge-based association mining study suggested several promising genes and gene-sets associated with HBV-related HCC risks, which would facilitate follow-up functional studies on the pathogenic mechanism of HCC.

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