Chen Yen-Yu, Chen Chi-Sheng, Huang Jee-Fu, Su Wen-Hsiu, Li Chia-Yang, Chen Wei-Shiun, Lin En-Sheng, Chuang Wan-Long, Yu Ming-Lung, Wang Shu-Chi
School of Medicine, Kaohsiung Medical University, Kaohsiung, 80756, Taiwan.
Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, 80756, Taiwan.
Hum Genet. 2025 Jan;144(1):1-14. doi: 10.1007/s00439-024-02686-x. Epub 2024 Jul 10.
The prevalence of overweight and obesity is increasing, leading to metabolic-associated fatty liver disease (MAFLD) characterized by excessive accumulation of liver fat and a risk of developing hepatocellular carcinoma (HCC). The driver gene mutations may play the roles of passengers that occur in single 'hotspots' and can promote tumorigenesis from benign to malignant lesions. We investigated the impact of high body weight and BMI on HCC survival using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset. To explore the effects of obesity-related gene mutations on HCC, we collected driver mutation genes in 34 TCGA patients with BMI ≥ 27 and 23 TCGA patients with BMI < 27. The digital PCR performing the PBMC samples for the variant rate by clinical cohort of 96 NAFLD patients. Our analysis showed that obesity leads to significantly worse survival outcomes in HCC. Using cbioportal, we identified 414 driver mutation genes in patients with obesity and 127 driver mutation genes in non-obese patients. Functional analysis showed that obese-related genes significantly enriched the regulated lipid and insulin pathways in HCC. The insulin secretion pathway in patients with obesity HCC-specific survival identified ABCC8 and PRKCB as significant genes (p < 0.001). It revealed significant differences in gene mutation and gene expression profiles compared to non-obese patients. The digital PCR test ABCC8 variants were detected in PBMC samples and caused a 14.5% variant rate, significantly higher than that of non-obese NAFLD patients. The study findings showed that the gene ABCC8 was a patient with the obesity-related gene in NAFLD, which provides the probability that ABCC8 mutation contributes to the pre-cancer lesion biomarker for HCC.
超重和肥胖的患病率正在上升，导致代谢相关脂肪性肝病（MAFLD），其特征是肝脏脂肪过度积累以及有发生肝细胞癌（HCC）的风险。驱动基因突变可能扮演发生在单个“热点”的过客角色，并可促进从良性病变到恶性病变的肿瘤发生。我们使用癌症基因组图谱肝细胞癌（TCGA-LIHC）数据集研究了高体重和BMI对HCC生存的影响。为了探究肥胖相关基因突变对HCC的影响，我们收集了34例BMI≥27的TCGA患者和23例BMI<27的TCGA患者中的驱动基因突变基因。通过96例非酒精性脂肪性肝病（NAFLD）患者的临床队列对PBMC样本进行数字PCR检测变异率。我们的分析表明，肥胖导致HCC患者的生存结果显著更差。使用cbioportal，我们在肥胖患者中鉴定出414个驱动基因突变基因，在非肥胖患者中鉴定出127个驱动基因突变基因。功能分析表明，肥胖相关基因在HCC中显著富集了调节脂质和胰岛素途径。肥胖HCC特异性生存患者的胰岛素分泌途径确定ABCC8和PRKCB为显著基因（p<0.0０1）。与非肥胖患者相比，它揭示了基因突变和基因表达谱的显著差异。在PBMC样本中检测到数字PCR测试ABCC8变异，变异率为14.5%，显著高于非肥胖NAFLD患者。研究结果表明，基因ABCC8是NAFLD中与肥胖相关的基因，这为ABCC8突变促成HCC癌前病变生物标志物提供了可能性。
