A Molecular Signature to Discriminate Dysplastic Nodules From Early Hepatocellular Carcinoma in HCV Cirrhosis

Josep M. Llovet, Yingbei Chen, Elisa Wurmbach, Sasan Roayaie, M. Isabel Fiel, Myron Schwartz, Swan N. Thung, Gregory Khitrov, Weijia Zhang, Augusto Villanueva, Carlo Battiston, Vincenzo Mazzaferro, Jordi Bruix, Samuel Waxman, Scott L. Friedman

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Abstract

Background & Aims: Small liver nodules ∼2 cm are difficult to characterize by radiologic or pathologic examination. Our aim was to identify a molecular signature to diagnose early hepatocellular carcinoma (HCC). Methods: The transcriptional profiles of 55 candidate genes were assessed by quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) in 17 dysplastic nodules (diameter, 10 mm) and 20 early HCC (diameter, 18 mm) from HCV cirrhotic patients undergoing resection/transplantation and 10 nontumoral cirrhotic tissues and 10 normal liver tissues. Candidate genes were confirmed by quantitative RT-PCR in 20 advanced HCCs and by immunohistochemistry in 75 samples and validated in an independent set of 29 samples (dysplastic nodules [10] and small HCC [19; diameter, 20 mm]). Results: Twelve genes were significantly, differentially expressed in early HCCs compared with dysplastic nodules (>2-fold change; area under the receiver operating characteristic curve ≥0.8): this included TERT, GPC3, gankyrin, survivin, TOP2A, LYVE1, E-cadherin, IGFBP3, PDGFRA, TGFA, cyclin D1, and HGF. Logistic regression analysis identified a 3-gene set including GPC3 (18-fold increase in HCC, P = .01), LYVE1 (12-fold decrease in HCC, P = .0001), and survivin (2.2-fold increase in HCC, P = .02), which had a discriminative accuracy of 94%. The validity of the gene signature was confirmed in a prospective testing set. GPC3 immunostaining was positive in all HCCs and negative in dysplastic nodules (22/22 vs 0/14, respectively, P <.001). Nuclear staining for survivin was positive in 12 of 13 advanced HCC cases and in 1 of 9 early tumors. Conclusions: Molecular data based on gene transcriptional profiles of a 3-gene set allow a reliable diagnosis of early HCC. Immunostaining of GPC3 confirms the diagnosis of HCC.

Original languageEnglish
Pages (from-to)1758-1767
Number of pages10
JournalGastroenterology
Volume131
Issue number6
DOIs
Publication statusPublished - Dec 2006

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ASJC Scopus subject areas

  • Gastroenterology

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Llovet, J. M., Chen, Y., Wurmbach, E., Roayaie, S., Fiel, M. I., Schwartz, M., Thung, S. N., Khitrov, G., Zhang, W., Villanueva, A., Battiston, C., Mazzaferro, V., Bruix, J., Waxman, S., & Friedman, S. L. (2006). A Molecular Signature to Discriminate Dysplastic Nodules From Early Hepatocellular Carcinoma in HCV Cirrhosis. Gastroenterology, 131(6), 1758-1767. https://doi.org/10.1053/j.gastro.2006.09.014