Hypoxia-induced gene expression in chemoradioresistant cervical cancer revealed by dynamic contrast-enhanced MRI.
Knowledge of the molecular background of functional magnetic resonance (MR) images is required to fully exploit their potential in cancer management. We explored the prognostic impact of dynamic contrast-enhanced MR imaging (DCE-MRI) parameters in cervical cancer combined with global gene expression data to reveal their underlying molecular phenotype and construct a representative gene signature for the relevant parameter. On the basis of 78 patients with cervical cancer subjected to curative chemoradiotherapy, we identified the prognostic DCE-MRI parameter A(Brix) by pharmacokinetic analysis of pretreatment images based on the Brix model, in which tumors with low A(Brix) appeared to be most aggressive. Gene set analysis of 46 tumors with pairwise DCE-MRI and gene expression data showed a significant correlation between A(Brix) and the hypoxia gene sets, whereas gene sets related to other tumor phenotypes were not significant. Hypoxia gene sets specific for cervical cancer created in cell culture experiments, including both targets of the hypoxia inducible factor (HIF1α) and the unfolded protein response, were the most significant. In the remaining 32 tumors, low A(Brix) was associated with upregulation of HIF1α protein expression, as assessed by immunohistochemistry, consistent with increased hypoxia. On the basis of the hypoxia gene sets, a signature of 31 genes that were upregulated in tumors with low A(Brix) was constructed. This DCE-MRI hypoxia gene signature showed prognostic impact in an independent validation cohort of 109 patients. Our findings reveal the molecular basis of an aggressive hypoxic phenotype and suggest the use of DCE-MRI to noninvasively identify patients with hypoxia-related chemoradioresistance.
Department of Radiation Biology, The Norwegian Radium Hospital, Nydalen, Norway.
Cathinka
C
Halle
Erlend
E
Andersen
Malin
M
Lando
Eva-Katrine
EK
Aarnes
Grete
G
Hasvold
Marit
M
Holden
Randi G
RG
Syljuåsen
Kolbein
K
Sundfør
Gunnar B
GB
Kristensen
Ruth
R
Holm
Eirik
E
Malinen
Heidi
H
Lyng
D003131:Combined Modality Therapy; D003287:Contrast Media; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000532:radiotherapy
D003287:Contrast Media