Hypoxia-driven gene expression is an independent prognostic factor in stage II and III colon cancer patients.
OBJECTIVE
Hypoxia is considered a major microenvironmental factor influencing cancer behavior. Our aim was to develop a hypoxia-based gene score that could identify high and low risk within stage II and III colon cancer patients.


METHODS
Differential gene expression of CaCo-2 colon cancer cells cultured in chronic hypoxia versus normoxia was tested for correlation with prognostic variables in published microarray datasets. These datasets were further used to downsize and optimize a gene score, which was subsequently determined in paraffin-embedded material of 126 patients with colon cancer treated in our center.


RESULTS
In the CaCo-2 cells, 923 genes with a 2-fold change and Limma corrected P ≤ 0.0001 were found differentially expressed in hypoxia versus normoxia. We identified 21 genes with prognostic value and overlapping in three different training sets and (n = 224). With a fourth published dataset (n = 177), the six-gene Colon Cancer Hypoxia Score (CCHS) was developed. Patients with low CCHS showed a significant better disease-free survival at three years (77.3%) compared with high CCHS patients (46.4%; log-rank, P = 0.006). This was independently confirmed in an external patient cohort of 90 stage II patients (86.9% vs. 52.2%; P = 0.001).


CONCLUSIONS
Hypoxia-driven gene expression is associated with high recurrence rates in stage II and III colon cancer. A six-gene score was found to be of independent prognostic value in these patients. Our findings require further validation and incorporation in the current knowledge on molecular classification of colon cancer.
Authors' Affiliations: Laboratory of Hepatology, Department of Clinical and Experimental Medicine, University Hospitals Leuven; Department of Electrical Engineering (ESAT), STADIUS-iMinds Future Health Department, KU Leuven; Departments of Abdominal Surgical Oncology; Imaging and Pathology, and Clinical Digestive Oncology, University Hospitals Leuven, Leuven, Belgium.
Jeroen
J
Dekervel
Daphne
D
Hompes
Hannah
H
van Malenstein
Dusan
D
Popovic
Xavier
X
Sagaert
Bart
B
De Moor
Eric
E
Van Cutsem
André
A
D'Hoore
Chris
C
Verslype
Jos
J
van Pelt
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018938:Caco-2 Cells; D015687:Cell Hypoxia; D015331:Cohort Studies; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D016014:Linear Models; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction