西班牙裔患者肝细胞癌的综合多组学特征分析

Integrative multi-omics characterization of hepatocellular carcinoma in Hispanic patients.

作者信息

Das Debodipta, Wang Xiaojing, Chiu Yu-Chiao, Bouamar Hakim, Sharkey Francis E, Lopera Jorge E, Lai Zhao, Weintraub Susan T, Han Xianlin, Zou Yi, Chen Hung-I H, Zeballos Torrez Carla R, Gu Xiang, Cserhati Matyas, Michalek Joel E, Halff Glenn A, Chen Yidong, Zheng Siyuan, Cigarroa Francisco G, Sun Lu-Zhe

机构信息

Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

出版信息

J Natl Cancer Inst. 2024 Dec 1;116(12):1961-1978. doi: 10.1093/jnci/djae207.

DOI:10.1093/jnci/djae207

PMID:39189979

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11630563/

Abstract

BACKGROUND

The incidence and mortality rates of hepatocellular carcinoma among Hispanic individuals in the United States are much higher than in non-Hispanic White people. We conducted multi-omics analyses to elucidate molecular alterations in hepatocellular carcinoma among Hispanic patients.

METHODS

Paired tumor and adjacent nontumor samples were collected from 31 Hispanic hepatocellular carcinomas in South Texas for genomic, transcriptomic, proteomic, and metabolomic profiling. Serum lipids were profiled in 40 Hispanic and non-Hispanic patients with or without clinically diagnosed hepatocellular carcinoma.

RESULTS

Exome sequencing revealed high mutation frequencies of AXIN2 and CTNNB1 in South Texas Hispanic hepatocellular carcinoma patients, suggesting a predominant activation of the Wnt/β-catenin pathway. TERT promoter mutations were also statistically significantly more frequent in the Hispanic cohort (Fisher exact test, P < .05). Cell cycles and liver function were positively and negatively enriched, respectively, with gene set enrichment analysis. Gene sets representing specific liver metabolic pathways were associated with dysregulation of corresponding metabolites. Negative enrichment of liver adipogenesis and lipid metabolism corroborated with a significant reduction in most lipids in serum samples of hepatocellular carcinoma patients (paired t test, P < .0001). Two hepatocellular carcinoma subtypes from our Hispanic cohort were identified and validated with the Cancer Genome Atlas liver cancer cohort. Patients with better overall survival showed higher activity of immune and angiogenesis signatures and lower activity of liver function-related gene signatures. They also had higher levels of immune checkpoint and immune exhaustion markers.

CONCLUSIONS

Our study revealed specific molecular features of Hispanic hepatocellular carcinoma and potential biomarkers for therapeutic management. It provides a unique resource for studying Hispanic hepatocellular carcinoma.

摘要

背景

美国西班牙裔个体中肝细胞癌的发病率和死亡率远高于非西班牙裔白人。我们进行了多组学分析，以阐明西班牙裔患者肝细胞癌中的分子改变。

方法

从南德克萨斯州的31例西班牙裔肝细胞癌患者中收集配对的肿瘤和癌旁非肿瘤样本，进行基因组、转录组、蛋白质组和代谢组分析。对40例有或无临床诊断肝细胞癌的西班牙裔和非西班牙裔患者进行血清脂质分析。

结果

外显子组测序显示，南德克萨斯州西班牙裔肝细胞癌患者中AXIN2和CTNNB1的突变频率较高，提示Wnt/β-连环蛋白通路主要激活。在西班牙裔队列中，TERT启动子突变在统计学上也显著更频繁（Fisher精确检验，P <.05）。通过基因集富集分析，细胞周期和肝功能分别呈正富集和负富集。代表特定肝脏代谢途径的基因集与相应代谢物的失调有关。肝细胞癌患者血清样本中大多数脂质显著减少，这与肝脏脂肪生成和脂质代谢的负富集一致（配对t检验，P <.0001）。我们在西班牙裔队列中鉴定出两种肝细胞癌亚型，并在癌症基因组图谱肝癌队列中得到验证。总生存期较好的患者显示出较高的免疫和血管生成特征活性以及较低的肝功能相关基因特征活性。他们还具有较高水平的免疫检查点和免疫耗竭标志物。