Development and validation of a 28-gene hypoxia signature for localised prostate cancer


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Lingjian Yang1,Darren Roberts1,Mandeep Takhar2,Nicholas Erho2,Vinayak Bhandari3,Becky Bibby1,Wei-Chen Cheng4,Syed Haider4,Amy McCorry5,Darragh McArt5,Suneil Jain5,Mohammed Alshalalfa2,Ashley Ross6,Edward Schaffer7,Robert Den8,R. Jeffrey Karnes9,Eric Klein10,Peter Hoskin11,Alastair Lamb12,David Neal4,Francesca Buffa4,Robert Bristow13,Paul Boutros3,Elai Davicioni2,Ananya Choudhury1,Catharine West1
1University of Manchester,2GenomeDX,3Ontario Institute for Cancer Research,4University of Oxford,5Queen’s University Belfast,6Johns Hopkins Medical Institutions,7Northwestern Feinberg School of Medicine,8Sidney Kimmel Medical College at Thomas Jefferson University,9Mayo Clinic Rochester,10Cleveland Clinic,11Mount Vernon Cancer Centre,12University of Cambridge,13University of Toronto

Abstract

Background

Hypoxia is associated with radiotherapy resistance and a poor prognosis in prostate cancer. There is evidence that only the most hypoxic tumours benefit from hypoxia-targeting treatment, but there is no clinically validated method identifying hypoxic prostate carcinoma. We aimed to derive and validate a hypoxia mRNA abundance signature in localised prostate cancer.

Method

RNA sequencing was used to identify genes regulated by hypoxia in vitro in four prostate cancer cell lines. in vitro hypoxia gene analysis was then combined with in vivo analysis of a gene co-expression network from primary prostate cancers to generate a hypoxia mRNA abundance signature. The signature was locked and independently validated in ten retrospective cohorts of patients with localised disease and outcome data. These cohorts reflected all risk groups where patients underwent either prostatectomy alone, prostatectomy and adjuvant radiotherapy, or radiotherapy alone. 

Results

A 28-gene signature was derived, of which 21 signature genes were regulated by hypoxia in vitro. Hypoxia signature score was positively associated with Gleason score, T stage but not pre-treatment PSA. Patients stratified as high hypoxia had significantly poorer biochemical recurrence free survival in eight independent cohorts of prostatectomy-treated patients (n=1176, P<10-11). The de novo signature was also an adverse prognostic factor in patients receiving post-prostatectomy radiotherapy (n=130, HR 2.82, 95% CI 1.33-6.00, P=0.007) or radiotherapy alone (n=248, log rank P=0.035). Prognostic significance remained after adjusting for Gleason score, T stage, and pre-treatment PSA. Prognostication improves when combined with a DNA genomic instability signature. The signature predicted benefit from hypoxia-modifying therapy in bladder cancer patients (intervention-by-signature interaction test P=0.0026), where carbogen and nicotinamide was associated with improved survival only in hypoxic tumours (n=113, HR 0.54, 95% CI 0.32-0.91, P=0.021).

Conclusion

A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients with primary tumours.