Abstract
Chronic infection with Hepatitis B virus (HBV) significantly increases the risk of hepatocellular carcinoma (HCC), particularly in Eastern Asia. However, only a subset of individuals with chronic HBV infection develop HCC, suggesting the role for genetic factors in HCC etiology. Despite genome-wide association studies (GWASs) identifying multiple single nucleotide polymorphisms (SNPs) associated with HBV-related HCC susceptibility, the underlying mechanisms and causal genetic polymorphisms remain largely unclear. To address this, we developed The Updated Integrative Functional Genomics Approach (TUIFGA), an methodology that combines data from transcription factor (TF) cistromics, ATAC-seq, DNAase-seq, and the 1000 Genomes Project to identify cancer susceptibility SNPs within TF-binding sites across human genome. Using TUIFGA, we discovered SNP rs13170300 which located in the TF MAZ binding motif of RPS14. The RPS14 rs13170300 was significantly associated with HCC risk in two case–control sets, with the T allele as the protective allele (Shandong discovery set: TT OR = 0.60, 95% CI = 0.49–0.74, P = 1.0 × 10–6; CT OR = 0.69, 95% CI = 0.55–0.86, P = 0.001; Jiangsu validation set: TT OR = 0.70, 95% CI = 0.56–0.87, P = 0.001; CT OR = 0.65, 95% CI = 0.53–0.82, P = 1.6 × 10–4). SNP rs13170300 affected MAZ binding in the RPS14 promoter, resulting in allele-specific changes in gene expression. RPS14 functions as a novel oncogene in HCC, specifically via activating the AKT signaling. Our findings present important insights into the functional genetics underlying HBV-related HCC development and may contribute to personalized approaches for cancer prevention and novel therapeutics.
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Data availability
The datasets produced in this study are available in Genome Sequence Archive-human HRA00564 (https://ngdc.cncb.ac.cn/gsa-human/).
Abbreviations
- ATAC-seq:
-
Assay for transposase-accessible chromatin using sequencing
- CI:
-
Confidence interval
- DNase-seq:
-
DNase I hypersensitive site sequencing
- eQTL:
-
Expression quantitative trait loci
- FC:
-
Fold change
- FBS:
-
Fetal bovine serum
- FPKM:
-
Fragments per kilobase of exon model per million reads mapped
- GWAS:
-
Genome-wide association studies
- HBV:
-
Hepatitis B virus
- HCC:
-
Hepatocellular carcinoma
- KEGG:
-
Kyoto encyclopedia of genes and genom
- LIHC:
-
Liver hepatocellular carcinoma
- MAF:
-
Minor allele frequency
- NC:
-
Negative control
- OR:
-
Odds ratios
- OS:
-
Overall survival
- PCR:
-
Polymerase chain reaction
- PFS:
-
Progression-free survival
- RT-qPCR:
-
Quantitative reverse transcription PCR
- siRNA:
-
Small interfering RNA
- SNP:
-
Single nucleotide polymorphisms
- TF:
-
Transcription factor
- TUIFGA:
-
The updated integrative functional genomics approach
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Acknowledgements
This work was supported by National Natural Science Foundation of China (82372760, 82173070 and 82103291); Natural Science Foundation of Shandong Province (ZR2021LZL004, ZR202102250889 and ZR202211010077); Major Scientific and Technological Innovation Project of Shandong Province (2021ZDSYS04); Taishan Scholars Program of Shandong Province (tsqn202211340 and tstp20221141); Program of Science and Technology for the youth innovation team in universities of Shandong Province (2020KJL001 and 2022KJ316). The authors would like to thank the many individuals who participated in the study. The authors have no conflicts of interest to disclose.
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MY conceived and designed this study. LH performed the experiments. MY, LH and YH acquired, analyzed, and interpreted the data from experiments. LH, YZ, and XY collected the human samples. MY, NZ, LH and YH drafted the manuscript. MY and NZ critically revised the manuscript for important intellectual content. MY supervised this study. All authors read and approved the final manuscript.
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Han, L., Huo, Y., Huang, L. et al. Genome-wide functional integration identified MAZ-controlled RPS14 dysregulation in hepatocellular carcinoma. Arch Toxicol 98, 985–997 (2024). https://doi.org/10.1007/s00204-023-03669-z
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DOI: https://doi.org/10.1007/s00204-023-03669-z