Gene Expression Signatures as Biomarkers of Tumour Hypoxia

Abstract

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.

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

“…Out of our classifier genes, only KCTD11 and P4HA2 were present in three (10)(11)(12) or one (11) of the six signatures, respectively. These results support the view that there are molecular differences in the aggressive hypoxic phenotype across cancers (19) and that cancer-type specific hypoxia gene classifiers are more effective (18). Furthermore, although some of the other signatures were statistically significantly correlated with A Brix (Supplementary Document S3), the signature of our classifier genes showed a stronger A Brix -association and was thus the best one for describing the aggressive phenotype reflected in the DCE-MR images of cervical cancer.…”

“…Among 32 signatures reviewed by Harris and colleagues (19), two of our six classifier genes, P4HA2 and ERO1A, are among the 20 most frequently appearing ones. The presence of common genes indicates that it might be possible to identify a signature that is applicable in different tumor sites, which has indeed been demonstrated in some cases (10,15,17,40,41).…”

“…Several hypoxia signatures have been constructed in different tissues (10)(11)(12)(13)(14)(15)(16)(17)(18), but a common cancer signature seems difficult to derive (19). The only hypoxia signature presented for cervical cancer was discovered in our previous work by combining global gene expression profiles and dynamic contrast enhanced (DCE)-MRI of the same patients (20).…”

Hypoxic microenvironment promotes proliferation and invasion of non-small cell lung cancer A549 Cells through Wnt/β-catenin signaling pathway

“…Abnormal proliferation and distant metastasis have been considered as the major factors leading to NSCLC-related death, which renders a great significance to the in-depth research into the molecular mechanism for ameliorating the clinical treatment and prognosis of patient with lung cancer. During the rapid growth of solid tumors, contradictions lie between the rapid proliferation and retarded peripheral vascular growth of tumor cells in a short time, which could result in insufficient nutrition and oxygen for tumor cells, thereby generating an ischemic and hypoxic microenvironment in focal tissues of tumor [6][7][8]. Furthermore, hypoxic microenvironment will affect cell proliferation, angiogenesis, invasion and metastasis of tumors [9][10][11].…”

Prognostic value of hypoxia-regulated gene expression in loco-regional gastroesophageal cancer

“…Thus, it has been shown to be prognostic in HNSCC [7], and a subset of genes from the signature was overlapping with other prognostic hypoxia signatures [9]. These overlapping genes included among others P4HA1, SLC2A1, BNIP3L, ALDOA and NDRG1, indicating that some genes are globally hypoxiainducible regardless of cancer type or underlying approach.…”