Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma.
Although HCC is the third-leading cause of cancer-related deaths worldwide, there is only an elemental understanding of its molecular pathogenesis. In western countries, HCV infection is the main etiology underlying this cancer's accelerating incidence. To characterize the molecular events of the hepatocarcinogenic process, and to identify new biomarkers for early HCC, the gene expression profiles of 75 tissue samples were analyzed representing the stepwise carcinogenic process from preneoplastic lesions (cirrhosis and dysplasia) to HCC, including 4 neoplastic stages (very early HCC to metastatic tumors) from patients with HCV infection. We identified gene signatures that accurately reflect the pathological progression of disease at each stage. Eight genes distinguish between control and cirrhosis, 24 between cirrhosis and dysplasia, 93 between dysplasia and early HCC, and 9 between early and advanced HCC. Using quantitative real-time reverse-transcription PCR, we validated several novel molecular tissue markers for early HCC diagnosis, specifically induction of abnormal spindle-like, microcephaly-associated protein, hyaluronan-mediated motility receptor, primase 1, erythropoietin, and neuregulin 1. In addition, pathway analysis revealed dysregulation of the Notch and Toll-like receptor pathways in cirrhosis, followed by deregulation of several components of the Jak/STAT pathway in early carcinogenesis, then upregulation of genes involved in DNA replication and repair and cell cycle in late cancerous stages.


CONCLUSIONS
These findings provide a comprehensive molecular portrait of genomic changes in progressive HCV-related HCC.
Wurmbach
Elisa
E
Mount Sinai Liver Cancer Program, Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA. elisa.wurmbach@mssm.edu
Chen
Ying-bei
YB
Khitrov
Greg
G
Zhang
Weijia
W
Roayaie
Sasan
S
Schwartz
Myron
M
Fiel
Isabel
I
Thung
Swan
S
Mazzaferro
Vincenzo
V
Bruix
Jordi
J
Bottinger
Erwin
E
Friedman
Scott
S
Waxman
Samuel
S
Llovet
Josep M
JM
D014408:Biomarkers, Tumor / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000821:virology; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018816:Genes, cdc; D015894:Genome, Human; D006526:Hepatitis C / Q000473:pathology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000821:virology
D014408:Biomarkers, Tumor