Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China.
Department of Endoscopy, Shandong Cancer Hospital and Institute, Jinan, Shandong, China.
Arch Toxicol. 2021 May;95(5):1621-1629. doi: 10.1007/s00204-021-03021-3. Epub 2021 Mar 13.
Transarterial chemoembolization (TACE) has significantly improved overall survival (OS) of unresectable hepatocellular carcinoma (HCC) patients. Unfortunately, a portion of patients show no therapeutic responses to TACE. N6-methyladenosine (mA) as well as its epigenetic writers, erasers, and readers play a crucial role in HCC development. However, it is still largely unclear how functional small nucleotide polymorphisms (SNPs) in mA-regulating genes contribute to prognosis of TACE-treated HCC patients. In this study, potential functional SNPs were systematically evaluated to identify their roles in the prognosis of HCC patients after TACE in a Chinese Han population. Employing multiple databases, we successfully annotated 55 candidate SNPs. After genotyping these SNPs in our TACE cohort, we identified three genetic variants in YTHDC2 (rs6594732, rs10071816, and rs2303718) and one SNP in FTO (rs7202116) having statistically significant associations with the OS of HCC patients treated with TACE. For example, multivariate Cox proportional hazards model indicated that the rs7202116 GG genotype carriers had markedly shorter OS and an 87% increased death risk compared with the AA carriers after TACE therapy (P = 0.002). When investigating functional relevance of these SNPs, we observed an allelic regulation of rs7202116 on FTO expression in HCC tissue samples, with higher tumor suppressor FTO expression among the A allele carriers. Our findings reported the first evidence supporting the prognostic value of mA reader YTHDC2 and mA eraser FTO SNPs in TACE-treated HCC patients. Importantly, our data implicated that mA-regulating genes may be targets to improve therapeutic strategy for unresectable HCC patients.
经导管动脉化疗栓塞术（TACE）显著改善了不可切除肝细胞癌（HCC）患者的总体生存率（OS）。不幸的是，部分患者对 TACE 没有治疗反应。N6-甲基腺苷（mA）及其表观遗传书写器、擦除器和读取器在 HCC 发展中起着至关重要的作用。然而，mA 调节基因中的功能性小核苷酸多态性（SNP）如何影响 TACE 治疗 HCC 患者的预后仍在很大程度上不清楚。在这项研究中，我们系统地评估了潜在的功能性 SNP，以确定它们在中国汉族人群中在 TACE 治疗后的 HCC 患者预后中的作用。我们利用多个数据库，成功注释了 55 个候选 SNP。在我们的 TACE 队列中对这些 SNP 进行基因分型后，我们在 YTHDC2 中发现了三个遗传变异（rs6594732、rs10071816 和 rs2303718）和一个 SNP（rs7202116）在 FTO 中，与 TACE 治疗的 HCC 患者的 OS 具有统计学显著关联。例如，多变量 Cox 比例风险模型表明，与 AA 携带者相比，rs7202116 GG 基因型携带者在 TACE 治疗后 OS 明显缩短，死亡风险增加 87%（P=0.002）。在研究这些 SNP 的功能相关性时，我们观察到 rs7202116 对 HCC 组织样本中 FTO 表达的等位基因调节，A 等位基因携带者中肿瘤抑制因子 FTO 的表达较高。我们的研究结果首次提供了支持 mA 读取器 YTHDC2 和 mA 擦除器 FTO SNP 在 TACE 治疗 HCC 患者中的预后价值的证据。重要的是，我们的数据表明 mA 调节基因可能是改善不可切除 HCC 患者治疗策略的靶点。
