Integrative genomic identification of genes on 8p associated with hepatocellular carcinoma progression and patient survival.
OBJECTIVE
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.
Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Stephanie
S
Roessler
Ezhou Lori
EL
Long
Anuradha
A
Budhu
Yidong
Y
Chen
Xuelian
X
Zhao
Junfang
J
Ji
Robert
R
Walker
Hu-Liang
HL
Jia
Qing-Hai
QH
Ye
Lun-Xiu
LX
Qin
Zhao-You
ZY
Tang
Ping
P
He
Kent W
KW
Hunter
Snorri S
SS
Thorgeirsson
Paul S
PS
Meltzer
Xin Wei
XW
Wang
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002681:China; D002872:Chromosome Deletion; D002898:Chromosomes, Human, Pair 8; D055028:Comparative Genomic Hybridization; D018450:Disease Progression; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D051548:Histone Acetyltransferases / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D008910:Minnesota; D015999:Multivariate Analysis; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011379:Prognosis; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; C485670:PLPBP protein, human; D011506:Proteins; C474507:SH2D4A protein, human; C486523:SORBS3 protein, human; D025521:Tumor Suppressor Proteins; C538729:ELP3 protein, human; D051548:Histone Acetyltransferases