Integrative genomic identification of genes on 8p associated with hepatocellular carcinoma progression and patient survival

Stephanie Roessler, Ezhou Lori Long, Anuradha Budhu, Yidong Chen, Xuelian Zhao, Junfang Ji, Robert Walker, Hu Liang Jia, Qing Hai Ye, Lun Xiu Qin, Zhao You Tang, Ping He, Kent W. Hunter, Snorri S. Thorgeirsson, Paul S. Meltzer, Xin Wei Wang

Research output: Contribution to journalArticle

181 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalGastroenterology
Volume142
Issue number4
DOIs
StatePublished - Apr 2012
Externally publishedYes

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Hepatocellular Carcinoma
Survival
Comparative Genomic Hybridization
Genes
Gene Expression
Neoplasms
Gene Dosage
Gene Expression Profiling
Virus Diseases
Multigene Family
Tumor Suppressor Genes
Hepatitis B virus
Chromosomes
In Vitro Techniques

Keywords

  • Cancer Driver Genes
  • Liver Cancer
  • Tumor Profiling

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Integrative genomic identification of genes on 8p associated with hepatocellular carcinoma progression and patient survival. / Roessler, Stephanie; Long, Ezhou Lori; Budhu, Anuradha; Chen, Yidong; Zhao, Xuelian; Ji, Junfang; Walker, Robert; Jia, Hu Liang; Ye, Qing Hai; Qin, Lun Xiu; Tang, Zhao You; He, Ping; Hunter, Kent W.; Thorgeirsson, Snorri S.; Meltzer, Paul S.; Wang, Xin Wei.

In: Gastroenterology, Vol. 142, No. 4, 04.2012.

Research output: Contribution to journalArticle

Roessler, S, Long, EL, Budhu, A, Chen, Y, Zhao, X, Ji, J, Walker, R, Jia, HL, Ye, QH, Qin, LX, Tang, ZY, He, P, Hunter, KW, Thorgeirsson, SS, Meltzer, PS & Wang, XW 2012, 'Integrative genomic identification of genes on 8p associated with hepatocellular carcinoma progression and patient survival', Gastroenterology, vol. 142, no. 4. https://doi.org/10.1053/j.gastro.2011.12.039
Roessler, Stephanie ; Long, Ezhou Lori ; Budhu, Anuradha ; Chen, Yidong ; Zhao, Xuelian ; Ji, Junfang ; Walker, Robert ; Jia, Hu Liang ; Ye, Qing Hai ; Qin, Lun Xiu ; Tang, Zhao You ; He, Ping ; Hunter, Kent W. ; Thorgeirsson, Snorri S. ; Meltzer, Paul S. ; Wang, Xin Wei. / Integrative genomic identification of genes on 8p associated with hepatocellular carcinoma progression and patient survival. In: Gastroenterology. 2012 ; Vol. 142, No. 4.
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abstract = "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.",
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AU - Roessler, Stephanie

AU - Long, Ezhou Lori

AU - Budhu, Anuradha

AU - Chen, Yidong

AU - Zhao, Xuelian

AU - Ji, Junfang

AU - Walker, Robert

AU - Jia, Hu Liang

AU - Ye, Qing Hai

AU - Qin, Lun Xiu

AU - Tang, Zhao You

AU - He, Ping

AU - Hunter, Kent W.

AU - Thorgeirsson, Snorri S.

AU - Meltzer, Paul S.

AU - Wang, Xin Wei

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N2 - 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.

AB - 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.

KW - Cancer Driver Genes

KW - Liver Cancer

KW - Tumor Profiling

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