Gene Expression Signatures as Biomarkers of Tumour Hypoxia

Hypoxia is a feature of most solid tumours and is associated with a poor prognosis. The hypoxic environment can reduce the efficacy of radiotherapy and some chemotherapeutics, and has been investigated extensively as a therapeutic target. The clinical use of hypoxia-targeting treatment will benefit from the development of a biomarker to assess tumour hypoxia. There are several possible techniques that measure either the level of oxygen or the tumour molecular response to hypoxia. The latter includes gene expression profiling, which measures the transcriptional response of a tumour to its hypoxic microenvironment. A systematic review identified 32 published hypoxia gene expression signatures. The methods used for their derivation varied, but are broadly classified as: (i) identifying genes with significantly higher or lower expression in cancer cells cultured under hypoxic versus normoxic conditions; (ii) using either previously characterised hypoxia-regulated genes/biomarkers to define hypoxic tumours and then identifying other genes that are over- or under-expressed in the hypoxic tumours. Both generated gene signatures useful in furthering our understanding of hypoxia biology. However, signatures derived using the second method seem to be superior in terms of providing prognostic information. Here we summarise all 32 published hypoxia signatures, discuss their commonalities and differences, and highlight their strengths and limitations. This review also highlights the importance of reproducibility and gene annotation, which must be accounted for to transfer signatures robustly for clinical application as biomarkers.