A Hypoxia Transcriptomic Signature Predicting Benefit from Hypoxia-modifying Treatment for High Risk Bladder Cancer Patients


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Lingjian Yang1,Amanda Williamson1,Joely Irlam1,Helen Denley2,Peter Hoskin3,Ananya Choudhury1,Catharine West1
1University of Manchester,2Manchester Royal Infirmary,3Mount Vernon Hospital

Abstract

Background

Hypoxia modification improves overall survival (OS) in muscle invasive bladder cancer patients who undergo radical radiotherapy. There is evidence that hypoxic tumours benefit most from hypoxia modification. The study aimed to identify or derive a hypoxia gene signature that predicts benefit from hypoxia-modifying treatment in bladder cancer.

Method

Bladder cancer transcriptomic data were available from public datasets and generated for 143 tumour samples from the BCON phase III trial of radiotherapy (RT) alone or with carbogen and nicotinamide (CON) using Affymetrix Human 1.0 Exon ST arrays. Published hypoxia signatures were tested. A novel signature was then derived by identifying candidate hypoxia genes from the literature and evaluating their bladder cancer specificity in the publically available datasets. A gene co-expression network was built and hub genes identified to generate a signature.

Results

None of the published hypoxia signatures were prognostic in public datasets or predicted benefit from hypoxia modification in BCON patients. A novel 17-gene signature was derived and cross validated by showing its prognostic significance in a surgical cohort. The signature was then independently validated in BCON patients. Patients categorised as high- versus low-hypoxia by the signature had a poor overall survival following radiotherapyalone (HR 2.80, 95% CI 1.48-5.32, P=0.0016). The signature also predicted benefit from CON with high-hypoxia patients receiving CON having a better overall survival than those receiving radiotherapy alone (HR 0.44, 95% CI 0.24-0.82, P=0.01). Prognostic and predictive significance remained after adjusting for clinicopathological variables (including gender, necrosis, age, stage and carcinoma in situ).

Conclusion

A 17-gene hypoxia signature has strong and independent prognostic and predictive value and has potential for individualising the treatment of patients with muscle invasive bladder cancer.