We have previously identified a prognostic 31-gene expression signature in locally advanced cervical cancer that is associated with tumor hypoxia and reflected by the dynamic contrast enhanced magnetic resonance (DCE-MR) image parameter ABrix. To bring the signature closer to clinical use, we here aimed to construct a classifier with key signature genes that retained an association to ABrix and separated the patients into groups with different hypoxia status and chemoradiotherapy outcome.
Integrative Analysis of DCE-MRI and Gene Expression Profiles in Construction of a Gene Classifier for Assessment of Hypoxia-Related Risk of Chemoradiotherapy Failure in Cervical Cancer.
Specimen part, Cell line
View SamplesThe present work aimed to identify reference genes for RT-qPCR studies of hypoxia in cervical cancer. From 422 candidate reference genes selected from the literature, we used Illumina array-based expression profiles to identify 182 genes not affected by hypoxia treatment in eight cervical cancer cell lines or correlated with the hypoxia-associated dynamic contrast-enhanced magnetic resonance imaging parameter ABrix in 42 patients. Among these genes, we selected nine candidates (CHCHD1, GNB2L1, IPO8, LASP1, RPL27A, RPS12, SOD1, SRSF9, TMBIM6) that were not associated with tumor volume, stage, lymph node involvement or disease progression in array data of 150 patients, for further testing by RT-qPCR. geNorm and NormFinder analyses of RT-qPCR data of 74 patients identified CHCHD1, SRSF9 and TMBIM6 as the most suitable set of reference genes, with stable expression both overall and across patient subgroups with different hypoxia status (ABrix) and clinical parameters. The suitability of the three candidates as reference genes were validated in studies of the hypoxia-induced genes DDIT3, ERO1A, and STC2. After normalizing with CHCHD1, SRSF9 and TMBIM6, the RT-qPCR data of these genes showed a significant correlation with Illumina expression (P<0.001, n=74) and ABrix (P<0.05, n=32), and the STC2 data were associated with clinical outcome, in accordance with the Illumina data. Thus, CHCHD1, SRSF9 and TMBIM6 seem to be suitable reference genes for studying hypoxia-related gene expression in cervical cancer samples by RT-qPCR. STC2 might be a useful prognostic hypoxia biomarker in cervical cancer that warrants further investigation.
Identification and Validation of Reference Genes for RT-qPCR Studies of Hypoxia in Squamous Cervical Cancer Patients.
Specimen part, Cell line
View SamplesWe performed integrative gene dosage and expression profiling to identify candidate target genes of the prognostic 3p loss in cervical cancer.
Identification of eight candidate target genes of the recurrent 3p12-p14 loss in cervical cancer by integrative genomic profiling.
Specimen part, Cell line
View SamplesWe 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 (HIF1) and the unfolded protein response (UPR), were the most significant. In the remaining 32 tumors, low ABrix was associated with upregulation of HIF1 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.
Hypoxia-induced gene expression in chemoradioresistant cervical cancer revealed by dynamic contrast-enhanced MRI.
Specimen part, Cell line, Treatment
View SamplesWe compared the prognostic significance of ectodomain isoforms of the epidermal growth factor receptor (EGFR), which lack the tyrosine kinase (TK) domain, with that of the full length receptor and its autophosphorylation status in cervical cancers treated with conventional chemoradiotherapy.
Membranous expression of ectodomain isoforms of the epidermal growth factor receptor predicts outcome after chemoradiotherapy of lymph node-negative cervical cancer.
Specimen part
View SamplesEmerging biomarkers based on medical images and molecular characterization of tumor biopsies open up for combining the two disciplines and exploiting their synergy in treatment planning. We compared pretreatment classification of cervical cancer patients by two previously validated imaging- and gene-based hypoxia biomarkers, evaluated the influence of intratumor heterogeneity, and investigated the benefit of combining them in prediction of treatment failure. The imaging-based biomarker was hypoxic fraction, determined from diagnostic dynamic contrast enhanced (DCE)-MR images. The gene-based biomarker was a hypoxia gene expression signature determined from tumor biopsies. Paired data were available for 118 patients. Intratumor heterogeneity was assessed by variance analysis of MR images and multiple biopsies from the same tumor. The two biomarkers were combined using a dimension-reduction procedure. The biomarkers classified 75% of the tumors with the same hypoxia status. Both intratumor heterogeneity and distribution pattern of hypoxia from imaging were unrelated to inconsistent classification by the two biomarkers, and the hypoxia status of the slice covering the biopsy region was representative of the whole tumor. Hypoxia by genes was independent on tumor cell fraction and showed minor heterogeneity across multiple biopsies in 9 tumors. This suggested that the two biomarkers could contain complementary biological information. Combination of the biomarkers into a composite score led to improved prediction of treatment failure (HR:7.3) compared to imaging (HR:3.8) and genes (HR:3.0) and prognostic impact in multivariate analysis with clinical variables. In conclusion, combining imaging- and gene-based biomarkers enables more precise and informative assessment of hypoxia-related treatment resistance in cervical cancer, independent of intratumor heterogeneity.
Combining imaging- and gene-based hypoxia biomarkers in cervical cancer improves prediction of chemoradiotherapy failure independent of intratumour heterogeneity.
Specimen part
View SamplesGene expression profiling of 82 patients with cervical cancer was performed. The expression data were correlated with copy number alterations of the same patients, as assessed with array CGH in a separate study, in order to identify drivers of cervical cancer carcinogenesis.
Gene network reconstruction reveals cell cycle and antiviral genes as major drivers of cervical cancer.
Specimen part
View SamplesTransformation of follicular lymphoma (FL) to a more aggressive disease is associated with rapid progression and death. Existing molecular markers for transformation are few and their clinical impact is limited. Here, we report on a whole-genome study of DNA copy numbers and gene expression profiles in serial FL biopsies. We identified 698 genes with high correlation between gene expression and copy number and the molecular network most enriched for these cis-associated genes. This network includes 14 cis-associated genes directly related to the NFB pathway. For each of these 14 genes, the correlated NFB target genes were identified and corresponding expression scores defined. The scores for six of the cis-associated NFB pathway genes (BTK, IGBP1, IRAK1, ROCK1, TMED7-TICAM2 and TRIM37) were significantly associated with transformation. The results suggest that genes regulating B-cell survival and activation are involved in transformation of FL
Whole-genome integrative analysis reveals expression signatures predicting transformation in follicular lymphoma.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Inhibition of Endothelial NOTCH1 Signaling Attenuates Inflammation by Reducing Cytokine-Mediated Histone Acetylation at Inflammatory Enhancers.
Specimen part
View SamplesWe aimed to investigate the transcriptional program associated with pimonidazole staining in prostate cancer.
The tumour hypoxia marker pimonidazole reflects a transcriptional programme associated with aggressive prostate cancer.
Specimen part, Cell line, Treatment
View Samples