Transcriptomics

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The hypoxia marker pimonidazole reflects a transcriptional program associated with aggressive prostate cancer.


ABSTRACT: We aimed to investigate the transcriptional program associated with pimonidazole staining in prostate cancer. A pimonidazole gene signature was identified that showed positive correlation to Ki67 labeling index, indicating increased proliferation in pimonidazole positive tumors. A positive correlation to clinical tumor stage and presence of lymph node metastasis was also found, consistent with associations between pimonidazole staining and clinico-pathological parameters. Moreover, the gene signature was associated with high Gleason score in a validation cohort of 59 patients and showed prognostic impact independent of Gleason score and other clinical markers in a watchful waiting validation cohort of 281 patients. Our work reveals the molecular basis of an aggressive prostate cancer phenotype reflected by pimonidazole staining, and suggests that genes involved in proliferation, DNA repair and hypoxia response contribute to this phenotype. We combined pimonidazole immunohistochemistry data and expression profiles to identify transcriptional program activated in pimonidazole positive tumors. Whole-genome gene expression profiles were determined in tumor biopsies from an investigation cohort of 46 patients, where 39 patients had received pimonidazole prior to surgery. Gene ontology analysis of 1046 genes upregulated in pimonidazole positive tumors, as defined by a staining fraction above 10%, showed significant enrichment of the biologic processes cell cycle, translation and cellular response to stress. Gene set analysis based on this result identified gene expressions in proliferation, DNA repair and hypoxia response as major parts of the transcriptional program associated with pimonidazole staining. Gene expression data of four prostate cancer cell lines were used to generate hypoxia response gene sets for this analysis. A signature of the 32 most essential genes in the program was constructed and shown to be associated with prostate cancer aggressiveness in two independent validation cohorts.

ORGANISM(S): Homo sapiens  

SUBMITTER: Knut H Hole   Heidi Lyng  Harald B Ragnum  Therese Seierstad  Ljiljana Vlatkovic  Karol Axcrona  Cathinka H Julin  Agnes K Lie  Kari-Anne M Frikstad 

PROVIDER: E-GEOD-55935 | ArrayExpress | 2015-01-05

SECONDARY ACCESSION(S): GSE55935PRJNA241350

REPOSITORIES: GEO, ArrayExpress

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The tumour hypoxia marker pimonidazole reflects a transcriptional programme associated with aggressive prostate cancer.

Ragnum H B HB   Vlatkovic L L   Lie A K AK   Axcrona K K   Julin C H CH   Frikstad K M KM   Hole K H KH   Seierstad T T   Lyng H H  

British journal of cancer 20141202 2


The hypoxia marker pimonidazole is a candidate biomarker of cancer aggressiveness. We investigated the transcriptional programme associated with pimonidazole staining in prostate cancer.Index tumour biopsies were taken by image guidance from an investigation cohort of 52 patients, where 43 patients received pimonidazole before prostatectomy. Biopsy location within the index tumour was verified for 46 (88%) patients, who were included for gene expression profiling and immunohistochemistry. Two in  ...[more]

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