BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is an aggressive malignancy; its mechanisms of development and progression are poorly understood. We used an integrative approach to identify HCC driver genes, defined as genes whose copy numbers associate with gene expression and cancer progression. METHODS: We combined data from high-resolution, array-based comparative genomic hybridization and transcriptome analysis of HCC samples from 76 patients with hepatitis B virus infection with data on patient survival times. Candidate genes were functionally validated using in vitro and in vivo models. RESULTS: Unsupervised analyses of array comparative genomic hybridization data associated loss of chromosome 8p with poor outcome (reduced survival time); somatic copy number alterations correlated with expression of 27.3% of genes analyzed. We associated expression levels of 10 of these genes with patient survival times in 2 independent cohorts (comprising 319 cases of HCC with mixed etiology) and 3 breast cancer cohorts (637 cases). Among the 10-gene signature, a cluster of 6 genes on 8p, (DLC1, CCDC25, ELP3, PROSC, SH2D4A, and SORBS3) were deleted in HCCs from patients with poor outcomes. In vitro and in vivo analyses indicated that the products of PROSC, SH2D4A, and SORBS3 have tumor-suppressive activities, along with the known tumor suppressor gene DLC1. CONCLUSIONS: We used an unbiased approach to identify 10 genes associated with HCC progression. These might be used in assisting diagnosis and to stage tumors based on gene expression patterns.
BACKGROUND & AIMS:Hepatocellular carcinoma (HCC) is an aggressive malignancy; its mechanisms of development and progression are poorly understood. We used an integrative approach to identify HCC driver genes, defined as genes whose copy numbers associate with gene expression and cancer progression. METHODS: We combined data from high-resolution, array-based comparative genomic hybridization and transcriptome analysis of HCC samples from 76 patients with hepatitis B virus infection with data on patient survival times. Candidate genes were functionally validated using in vitro and in vivo models. RESULTS: Unsupervised analyses of array comparative genomic hybridization data associated loss of chromosome 8p with poor outcome (reduced survival time); somatic copy number alterations correlated with expression of 27.3% of genes analyzed. We associated expression levels of 10 of these genes with patient survival times in 2 independent cohorts (comprising 319 cases of HCC with mixed etiology) and 3 breast cancer cohorts (637 cases). Among the 10-gene signature, a cluster of 6 genes on 8p, (DLC1, CCDC25, ELP3, PROSC, SH2D4A, and SORBS3) were deleted in HCCs from patients with poor outcomes. In vitro and in vivo analyses indicated that the products of PROSC, SH2D4A, and SORBS3 have tumor-suppressive activities, along with the known tumor suppressor gene DLC1. CONCLUSIONS: We used an unbiased approach to identify 10 genes associated with HCC progression. These might be used in assisting diagnosis and to stage tumors based on gene expression patterns.
Authors: Lisa M McShane; Michael D Radmacher; Boris Freidlin; Ren Yu; Ming-Chung Li; Richard Simon Journal: Bioinformatics Date: 2002-11 Impact factor: 6.937
Authors: Marian E Durkin; Bao-Zhu Yuan; Xiaoling Zhou; Drazen B Zimonjic; Douglas R Lowy; Snorri S Thorgeirsson; Nicholas C Popescu Journal: J Cell Mol Med Date: 2007 Sep-Oct Impact factor: 5.310
Authors: Jana Samarin; Vibor Laketa; Mona Malz; Stephanie Roessler; Ilan Stein; Elad Horwitz; Stephan Singer; Eleni Dimou; Antonio Cigliano; Michaela Bissinger; Christine Susanne Falk; Xin Chen; Steven Dooley; Eli Pikarsky; Diego Francesco Calvisi; Carsten Schultz; Peter Schirmacher; Kai Breuhahn Journal: Hepatology Date: 2016-01-14 Impact factor: 17.425
Authors: Fumin Lin; Kathrina L Marcelo; Kimal Rajapakshe; Cristian Coarfa; Adam Dean; Nathaniel Wilganowski; Holly Robinson; Eva Sevick; Karl-Dimiter Bissig; Lauren C Goldie; Anthony R Means; Brian York Journal: Hepatology Date: 2015-05-09 Impact factor: 17.425
Authors: Colin M Court; Shuang Hou; Lian Liu; Paul Winograd; Benjamin J DiPardo; Sean X Liu; Pin-Jung Chen; Yazhen Zhu; Matthew Smalley; Ryan Zhang; Saeed Sadeghi; Richard S Finn; Fady M Kaldas; Ronald W Busuttil; Xianghong J Zhou; Hsian-Rong Tseng; James S Tomlinson; Thomas G Graeber; Vatche G Agopian Journal: NPJ Precis Oncol Date: 2020-07-02