Hypoxia-induced gene expression in chemoradioresistant cervical cancer revealed by dynamic contrast enhanced MRI
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ABSTRACT: We explored the prognostic impact of the dynamic contrast enhanced MR imaging (DCE-MRI) parameter ABrix in cervical cancer combined with global gene expression data to reveal the underlying molecular phenotype of the parameter and construct a gene signature that reflected ABrix. Based on 78 cervical cancer patients subjected to curative chemoradiotherapy, we identified a prognostic ABrix parameter by pharmacokinetic analysis of DCE-MR images based on the Brix model, where tumors with low ABrix appeared to be most aggressive. Gene set enrichment analysis of 46 tumors with pairwise DCE-MRI and gene expression data showed a significant correlation between ABrix and the hypoxia gene sets, whereas gene sets related to proliferation, radioresistance, and wound healing were not significant. Hypoxia gene sets specific for cervical cancer created in cell culture experiments, including targets of the hypoxia inducible factor (HIF1M-NM-1) and the unfolded protein response (UPR), were the most significant. In the remaining 32 tumors, low ABrix was associated with upregulation of HIF1M-NM-1 protein expression, as assessed by immunohistochemistry, consistent with increased hypoxia. Based on the hypoxia gene sets, a signature of 31 genes that were upregulated in tumors with low ABrix was constructed. This DCE-MRI hypoxia gene signature showed prognostic impact in an independent validation cohort of 109 patients. Gene expression correlating with the DCE-MRI parameter ABrix were identified in 46 patients (DCE-MRI cohort) and used to find a hypoxia gene signature. The prognsotic impact of the gene signature was validated in an independent cohort of 109 patients (validation chort). Cell culture experiments were performed to generate cervical cancer specific gene lists associated with hypoxia (GSM897799 - GSM897804).
ORGANISM(S): Homo sapiens
SUBMITTER: Heidi Lyng
PROVIDER: E-GEOD-36562 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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