Open AccessA Survey of Molecular Heterogeneity in Hepatocellular Carcinoma
Author(s) -
Jovel Juan,
Lin Zhen,
O'keefe Sandra,
Willows Steven,
Wang Weiwei,
Zhang Guangzhi,
Patterson Jordan,
MoctezumaVelázquez Carlos,
Kelvin David J.,
KaShu Wong Gane,
Mason Andrew L.
Publication year - 2018
Publication title -
hepatology communications
Language(s) - English
Resource type - Journals
ISSN - 2471-254X
DOI - 10.1002/hep4.1197
Subject(s) - biology , cancer research , tensin , pten , pdgfra , carcinogenesis , gene , genetics , pi3k/akt/mtor pathway , signal transduction , stromal cell , gist
Understanding the heterogeneity of dysregulated pathways associated with the development of hepatocellular carcinoma (HCC) may provide prognostic and therapeutic avenues for disease management. As HCC involves a complex process of genetic and epigenetic modifications, we evaluated expression of both polyadenylated transcripts and microRNAs from HCC and liver samples derived from two cohorts of patients undergoing either partial hepatic resection or liver transplantation. Copy number variants were inferred from whole genome low‐pass sequencing data, and a set of 56 cancer‐related genes were screened using an oncology panel assay. HCC was associated with marked transcriptional deregulation of hundreds of protein‐coding genes. In the partially resected livers, diminished transcriptional activity was observed in genes associated with drug catabolism and increased expression in genes related to inflammatory responses and cell proliferation. Moreover, several long noncoding RNAs and microRNAs not previously linked with HCC were found to be deregulated. In liver transplant recipients, down‐regulation of genes involved in energy production and up‐regulation of genes associated with glycolysis were detected. Numerous copy number variants events were observed, with hotspots on chromosomes 1 and 17. Amplifications were more common than deletions and spanned regions containing genes potentially involved in tumorigenesis. Colony stimulating factor 1 receptor ( CSF1R ), fibroblast growth factor receptor 3 ( FGFR3 ), fms‐like tyrosine kinase 3 ( FLT3 ), nucleolar phosphoprotein B23 ( NPM1 ), platelet‐derived growth factor receptor alpha polypeptide ( PDGFRA ), phosphatase and tensin homolog ( PTEN ), G‐protein‐coupled receptors‐like receptor Smoothened ( SMO ), and tumor protein P53 ( TP53 ) were mutated in all tumors; another 26 cancer‐related genes were mutated with variable penetrance. Conclusion : Our results underscore the marked molecular heterogeneity between HCC tumors and reinforce the notion that precision medicine approaches are needed for management of individual HCC. These data will serve as a resource to generate hypotheses for further research to improve our understanding of HCC biology. ( Hepatology Communications 2018; 00:000‐000)