A seven-gene set associated with chronic hypoxia of prognostic importance in hepatocellular carcinoma.
OBJECTIVE
Hepatocellular carcinomas (HCC) have an unpredictable clinical course, and molecular classification could provide better insights into prognosis and patient-directed therapy. We hypothesized that in HCC, certain microenvironmental regions exist with a characteristic gene expression related to chronic hypoxia which would induce aggressive behavior.


METHODS
We determined the gene expression pattern for human HepG2 liver cells under chronic hypoxia by microarray analysis. Differentially expressed genes were selected and their clinical values were assessed. In our hypothesis-driven analysis, we included available independent microarray studies of patients with HCC in one single analysis. Three microarray studies encompassing 272 patients were used as training sets to determine a minimal prognostic gene set, and one recent study of 91 patients was used for validation.


RESULTS
Using computational methods, we identified seven genes (out of 3,592 differentially expressed under chronic hypoxia) that showed correlation with poor prognostic indicators in all three training sets (65/139/73 patients) and this was validated in a fourth data set (91 patients). Retrospectively, the seven-gene set was associated with poor survival (hazard ratio, 1.39; P = 0.007) and early recurrence (hazard ratio, 2.92; P = 0.007) in 135 patients. Moreover, using a hypoxia score based on this seven-gene set, we found that patients with a score of >0.35 (n = 42) had a median survival of 307 days, whereas patients with a score of < or =0.35 (n = 93) had a median survival of 1,602 days (P = 0.005).


CONCLUSIONS
We identified a unique, liver-specific, seven-gene signature associated with chronic hypoxia that correlates with poor prognosis in HCCs.
van Malenstein
Hannah
H
Department of Digestive Oncology, University Hospital Gasthuisberg, Belgium.
Gevaert
Olivier
O
Libbrecht
Louis
L
Daemen
Anneleen
A
Allemeersch
Joke
J
Nevens
Frederik
F
Van Cutsem
Eric
E
Cassiman
David
D
De Moor
Bart
B
Verslype
Chris
C
van Pelt
Jos
J
D019540:Area Under Curve; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality; D015687:Cell Hypoxia / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012372:ROC Curve