Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

Abstract

SUMMARY Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole exome sequencing and DNA copy number analyses, and 196 HCC also by DNA methylation, RNA, miRNA, and proteomic expression. DNA sequencing and mutation analysis identified significantly mutated genes including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or down-regulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.

Telomerase reverse transcriptase mutations in plasma DNA in patients with hepatocellular carcinoma or cirrhosis: Prevalence and risk factors

“…Two TERT promoter mutations, chr5 1,295,228 G>A (C228T) and 1,295,250 G>A (C250T), were measured by Sanger sequencing in 196 patients with HCC in TCGA and recently reported 6. The clinical and demographic characterization of these 196 patients are summarized in http://onlinelibrary.wiley.com/doi/10.1002/hep4.1187/full.…”

“…The Cancer Genome Atlas (TCGA) HCC data were extracted from a recent study,6 the http://www.cbioportal.org/, and http://firebrowse.org/ 10. Clinical and demographic parameters from 196 HCCs with available TERT promoter mutations data in TCGA are summarized in http://onlinelibrary.wiley.com/doi/10.1002/hep4.1187/full.…”

“…Samples with a mutant TERT allele fraction ≥0.1% and with at least two visible mutant signals were considered positive for the mutation, as described 11, 12. Because the two TERT promoter mutations are mutually exclusive,6, 7 we measured TERT C250T mutation in samples that were negative for TERT C228T mutation.…”

“…Recent genomic studies have identified telomerase reverse transcriptase ( TERT ), tumor protein p53 ( TP53 ), and catenin beta 1 (CTNNB1) as the most frequently mutated genes in HCC 4, 5, 66, 7 and a central and ancestry‐independent node of hepatocarcinogenesis 4.…”

“…TERT promoter mutation is the most frequent genetic alteration in HCC6, 7 and a central and ancestry‐independent node of hepatocarcinogenesis 4. Most importantly, TERT promoter mutations occur also in cirrhotic preneoplastic macronodules (25%) and in hepatocellular adenomas with malignant transformation to HCC (44%), therefore representing early recurrent genetic events in HCC in the cirrhotic and noncirrhotic liver 7, 8.…”