Genomic and Epigenomic Features of Primary and Recurrent Hepatocellular Carcinomas

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal

7 Scopus Citations
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Author(s)

  • Xiaofan Ding
  • Mian He
  • Anthony W.H. Chan
  • Qi Xiu Song
  • Siu Ching Sze
  • Hui Chen
  • Matthew K.H. Man
  • Kwan Man
  • Stephen L. Chan
  • Paul B.S. Lai
  • Nathalie Wong

Related Research Unit(s)

Detail(s)

Original languageEnglish
Pages (from-to)1630-1645
Journal / PublicationGastroenterology
Volume157
Issue number6
Online published24 Sep 2019
Publication statusPublished - Dec 2019

Abstract

BACKGROUND & AIMS: Intratumor heterogeneity and divergent clonal lineages within and among primary and recurrent hepatocellular carcinomas (HCCs) produce challenges to patient management. We investigated genetic and epigenetic variations within liver tumors, among hepatic lesions, and between primary and relapsing tumors. METHODS: Tumor and matched nontumor liver specimens were collected from 113 patients who underwent partial hepatectomy for primary or recurrent HCC at 2 hospitals in Hong Kong. We performed whole-genome, whole-exome, or targeted capture sequencing analyses of 356 HCC specimens collected from multiple tumor regions and matched initial and recurrent tumors. We performed parallel DNA methylation profiling analyses of 95 specimens. Genomes and epigenomes of nontumor tissues that contained areas of cirrhosis or fibrosis were analyzed. We developed liver cancer cell lines that endogenously expressed a mutant form of TP53 (R249S) or overexpressed mutant forms of STAT3 (D170Y, K348E, and Y640F) or JAK1 (S703I and L910P) and tested the abilities of pharmacologic agents to reduce activity. Cells were analyzed by immunoblotting and chromatin immunoprecipitation with quantitative polymerase chain reaction. RESULTS: We determined the monoclonal origins of individual tumors using a single sample collection approach that captured more than 90% of mutations that are detected in all regions of tumors. Phylogenetic and phyloepigenetic analyses revealed interactions and codependence between the genomic and epigenomic features of HCCs. Methylation analysis revealed a field effect in cirrhotic liver tissues that predisposes them to tumor development. Comparisons of genetic features revealed that 52% of recurrent HCCs derive from the clonal lineage of the initial tumor. The clonal origin if recurrent HCCs allowed construction of a temporal map of genetic alterations that associated with tumor recurrence. Activation of JAK signaling to STAT was a characteristic of HCC progression via mutations that associate with response to drug sensitivity. The combination of a mutation that increases the function of TP53 and the 17p chromosome deletion might provide liver cancer cells with a replicative advantage. Chromatin immunoprecipitation analysis of TP53 with the R249S substitution revealed its interaction with genes that encode chromatin regulators (MLL1 and MLL2). We validated MLL1 and MLL2 as direct targets of TP53(R249S) and affirmed their association in the Cancer Genome Atlas dataset. The MLL-complex antagonists MI-2-2 (inhibitor of protein interaction) and OICR-9492 (inhibitor of activity) specifically inhibited proliferation of HCC cells that express TP53(R249S) at nanomolar concentrations. CONCLUSIONS: We performed a systematic evaluation of intra- and intertumor genetic heterogeneity in HCC samples and identified genetic and epigenetic changes that associate with tumor progression and recurrence. We identified chromatin regulators that are upregulated by mutant TP53 in HCC cells and inhibitors that reduce proliferation of these cells. DNA methylation patterns in cirrhotic or fibrotic liver tissues might be used to identify those at risk of HCC development.

Research Area(s)

  • Hepatic Carcinogenesis, Treatment, Tumor Progression, Tumorigenesis

Citation Format(s)

Genomic and Epigenomic Features of Primary and Recurrent Hepatocellular Carcinomas. / Ding, Xiaofan; He, Mian; Chan, Anthony W.H.; Song, Qi Xiu; Sze, Siu Ching; Chen, Hui; Man, Matthew K.H.; Man, Kwan; Chan, Stephen L.; Lai, Paul B.S.; Wang, Xin; Wong, Nathalie.

In: Gastroenterology, Vol. 157, No. 6, 12.2019, p. 1630-1645.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal