Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a high mortality rate. The 5-methylcytosine (m5C), a type of RNA modification, plays crucial regulatory roles in HCC carcinogenesis, metastasis, and prognosis. However, a few studies have investigated the effect of genetic variants in m5C modification genes on survival of patients with hepatitis B virus (HBV)-related HCC. In the present study, we evaluated associations between 144 SNPs in 15 m5C modification genes and overall survival (OS) in 866 patients with the HBV-related HCC. Expression quantitative trait loci (eQTL) analysis and differential expression analysis were conducted to investigate biological mechanisms. As a result, we identified that two SNPs (NSUN7 rs2437325 A > G and TRDMT1 rs34434809 G > C) were significantly associated with HBV-related HCC OS with adjusted allelic hazards ratios of 1.25 (95% confidence interval = 1.05–1.48 and P = 0.011) and 1.19 (1.02–1.38 and P = 0.027), respectively, with a trend of combined risk genotypes (Ptrend < 0.001). Moreover, the results of eQTL analyses showed that both NSUN7 rs2437325 G and TRDMT1 rs34434809 C alleles were associated with a reduced mRNA expression level in 208 normal liver tissues (P = 0.007 and P < 0.001, respectively). Taken together, genetic variants in the m5C modification genes may be potential prognostic biomarkers of HBV-related HCC after hepatectomy, likely through mediating the mRNA expression of corresponding genes.
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Data availability
The datasets generated and/or analysed during the current study are not publicly available due [REASON WHY DATA ARE NOT PUBLIC] but are available from the corresponding author on reasonable request.
References
Aguilo F, Li S, Balasubmmaniyan N et al (2016) Deposition of 5-methylcytosine on enhancer RNAs enables the coactivator function of PGc-10. Cell Rep 14:479–492. https://doi.org/10.1016/j.celrep.2015.12.043
Bohnsack K, Höbartner C, Bohnsack M (2019) Eukaryotic 5-methylcytosine (m5C) RNA methyltransferases: mechanisms, cellular functions, and links to disease. Genes 10(2):102. https://doi.org/10.3390/genes10020102
Chang J, Lin L, Zhou C et al (2023) Functional polymorphisms of the TET1 gene increase the risk of neuroblastoma in Chinese children. J Cell Mol Med 27(15):2239–2248. https://doi.org/10.1111/jcmm
Chen H, Yang H, Zhu X et al (2020) M5C modification of mRNA serves a DNA damage code to promote homologous recombination. Nat Commun 11(1):2834. https://doi.org/10.1038/s41467-020-16722-7
Elhardt W, Shanmugam R, Jurkowski TP et al (2015) Somatic cancer mutations in the DNMT2 tRNA methyltransferase alter its catalytic properties. Biochimie 112:66–72. https://doi.org/10.1016/j.biochi.2015.02.022
García-Vílchez R, Sevilla A, Blanco S (2019) Post-transcriptional regulation by cytosine-5 methylation of RNA. Biochim Biophys Acta Gene Regul Mech 1862:240–252. https://doi.org/10.1016/j.bbagrm.2018.12.003
Huang Q (2015) Genetic study of complex diseases in the post-GWAS era. J Genet Genomics 42(3):87–98. https://doi.org/10.1016/j.jgg.2015.02.00
Huang Q, Liu Y, Qiu M et al (2022) Potentially functional variants of MAP3K14 in the NF-κB signaling pathway genes predict survival of HBV-related hepatocellular carcinoma patients. Front Oncol 12:990160. https://doi.org/10.3389/fonc.2022.990160
Jiang D, Zhang L, Liu W et al (2021) Trends in cancer mortality in China from 2004 to 2018: a nationwide longitudinal study. Cancer Commun 41(10):1024–1036. https://doi.org/10.1002/cac2.12195
Lewinska A, Adamczyk-Grochala J, Wnuk M (2023) TRDMT1-mediated RNA C-5 methylation as a novel target in anticancer therapy. Biochim Biophys Acta Rev Cancer. https://doi.org/10.1016/j.bbcan.2023.188964
Li Y, Zhai Y, Song Q et al (2018) Genome-wide association study identifies a new locus at 7q21.13 associated with hepatitis b virus-related hepatocellular carcinoma. Clin Cancer Res 24(4):906–915. https://doi.org/10.1158/1078-0432.CCR-17-2537
Li D, Li K, Zhang W et al (2022a) The m6A/m5C/m1A regulated gene signature predicts the prognosis and correlates with the immune status of hepatocellular carcinoma. Front Immunol 6:918140. https://doi.org/10.3389/fimmu.2022.918140
Li M, Tao Z, Zhao Y et al (2022b) 5-methylcytosine RNA methyltransferases and their potential roles in cancer. J Transl Med 20(1):214. https://doi.org/10.1186/s12967-022-03427-2
Lin L, Deng C, Zhou C et al (2023a) NSUN2 gene rs13181449 C>T polymorphism reduces neuroblastoma risk. Gene 20(854):147120. https://doi.org/10.1016/j.gene.2022.147120
Lin L, Wang B, Zhang X et al (2023b) Functional TET2 gene polymorphisms increase the risk of neuroblastoma in Chinese children. IUBMB Life. https://doi.org/10.1002/iub.2791
Llovet JM, Kelley RK, Villanueva A et al (2021) Hepatocellular carcinoma. Nat Rev Dis Primers 7(1):6. https://doi.org/10.1038/s41572-020-00240-3
Ortiz-Barahona V, Soler M, Davalos V et al (2023) Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer. Mol Cancer 22(1):83. https://doi.org/10.1186/s12943-023-01785-z
Sato K, Tahata K, Akimoto K (2020) Five genes associated with survival in patients with lower-grade gliomas were identified by information-theoretical analysis. Anticancer Res 40:2777–2785. https://doi.org/10.21873/anticanres.14250
Sun Z, Xue S, Zhang M et al (2020) Aberrant NSUN2-mediated m5C modification of H19 lncRNA is associated with poor differentiation of hepatocellular carcino. Oncogene 39(45):6906–6919. https://doi.org/10.1038/s41388-020-01475-w
Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality world-wide for 36 cancers in 185 Countrie. CA Cancer J Clin 71(3):209–249. https://doi.org/10.3322/caac.21660
Vivekanandan P, Daniel HD, Kannangai R et al (2010) Hepatitis B virus replication induces methylation of both host and viral DNA. J Virol 84(9):4321–4329. https://doi.org/10.1128/JVI.02280-09
Wakefield J (2007) A Bayesian measure of the probability of false discovery in genetic epidemiology studies. Am J Hum Genet 81(2):208–227. https://doi.org/10.1086/519024
Wang S, Du X, Han X et al (2018) Influence of socioeconomic events on cause-specific mortality in urban Shanghai, China, from 1974 to2015: a population-based longitudinal study. CMAJ 190(39):E1153–E1161. https://doi.org/10.1503/cmaj.180272
Wei J, Sheng Y, Li J et al (2019) Genome-wide association study identifies a genetic prediction model for postoperative survival in patients with hepatocellular carcinoma. Med Sci Monit 25:2452–2478. https://doi.org/10.12659/MSM.915511
Yang X, Yang F, Lan L et al (2022) Diagnostic and prognostic value of m5C regulatory genes in hepatocellular carcinoma. Front Genet 13:972043. https://doi.org/10.3389/fgene.2022.972043
Zhang D, Guo S, Schrodi SJ (2021) Mechanisms of DNA methylation in virus-host interaction in hepatitis B infection: pathogenesis and oncogenetic properties. Int J Mol Sci 22(18):9858. https://doi.org/10.3390/ijms22189858
Zhu X, Wang Z, Qiu X et al (2017) Associations between single-nucleotide polymorphisms in RYBP and the prognosis of hepatocellular carcinoma in a Chinese population. Carcinogenesis 38(5):532–540. https://doi.org/10.1093/carcin/bgx031
Zhu X, Wang Z, Qiu X et al (2018) Rs2303428 of Msh2 is associated with hepatocellular carcinoma prognosis in a Chinese population. DNA Cell Biol 37(7):634–641. https://doi.org/10.1089/dna.2018.4224
Acknowledgements
This study was supported by grants from the Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education (GKE-ZZ202316); Youth Science Foundation of Guangxi Medical University (GXMUYSF202312); Youth Program of Scientific Research Foundation of Guangxi Medical University Cancer Hospital (YQJ2022-5); Youth Science Foundation of Guangxi Medical University (GXMUYSF202304); The 111 Projects (D17011).
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Research ideas: BWC, MQQ, RBG, and QLL; investigation: YCL, ZHZ, WML, and YJJ; scheme design: YYW, QGH, and QYM. Data analysis: QPW and XXW; writing—original draft: BWC, MQQ, and RBG; writing—review & editing: QLL and HPY; resource: HPY.
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Chen, B., Qiu, M., Gong, R. et al. Genetic variants in m5C modification genes are associated with survival of patients with HBV-related hepatocellular carcinoma. Arch Toxicol 98, 1125–1134 (2024). https://doi.org/10.1007/s00204-024-03687-5
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DOI: https://doi.org/10.1007/s00204-024-03687-5