Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer

Lingjian Yang; Darren Roberts; Mandeep Takhar; Nicholas Erho; Becky A.S. Bibby; Niluja Thiruthaneeswaran; Vinayak Bhandari; Wei Chen Cheng; Syed Haider; Amy M.B. McCorry; Darragh McArt; Suneil Jain; Mohammed Alshalalfa; Ashley Ross; Edward Schaffer; Robert B. Den; R. Jeffrey Karnes; Eric Klein; Peter J. Hoskin; Stephen J. Freedland; Alastair D. Lamb; David E. Neal; Francesca M. Buffa; Robert G. Bristow; Paul C. Boutros; Elai Davicioni; Ananya Choudhury; Catharine M.L. West

doi:10.1016/j.ebiom.2018.04.019

Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer

Lingjian Yang, Darren Roberts, Mandeep Takhar, Nicholas Erho, Becky A.S. Bibby, Niluja Thiruthaneeswaran, Vinayak Bhandari, Wei Chen Cheng, Syed Haider, Amy M.B. McCorry, Darragh McArt, Suneil Jain, Mohammed Alshalalfa, Ashley Ross, Edward Schaffer, Robert B. Den, R. Jeffrey Karnes, Eric Klein, Peter J. Hoskin, Stephen J. FreedlandAlastair D. Lamb, David E. Neal, Francesca M. Buffa, Robert G. Bristow, Paul C. Boutros, Elai Davicioni, Ananya Choudhury, Catharine M.L. West^*

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

Background: Hypoxia is associated with a poor prognosis in prostate cancer. This work aimed to derive and validate a hypoxia-related mRNA signature for localized prostate cancer. Method: Hypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signature. The signature was independently validated in eleven prostate cancer cohorts and a bladder cancer phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON). Results: A 28-gene signature was derived. Patients with high signature scores had poorer biochemical recurrence free survivals in six of eight independent cohorts of prostatectomy-treated patients (Log rank test P <.05), with borderline significances achieved in the other two (P <.1). The signature also predicted biochemical recurrence in patients receiving post-prostatectomy radiotherapy (n = 130, P =.007) or definitive radiotherapy alone (n = 248, P =.035). Lastly, the signature predicted metastasis events in a pooled cohort (n = 631, P =.002). Prognostic significance remained after adjusting for clinic-pathological factors and commercially available prognostic signatures. The signature predicted benefit from hypoxia-modifying therapy in bladder cancer patients (intervention-by-signature interaction test P =.0026), where carbogen and nicotinamide was associated with improved survival only in hypoxic tumours. Conclusion: A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients.

Original language	English (US)
Pages (from-to)	182-189
Number of pages	8
Journal	EBioMedicine
Volume	31
DOIs	https://doi.org/10.1016/j.ebiom.2018.04.019
State	Published - May 2018

Keywords

Gene expression signature
Hypoxia
Prognostic biomarker
Prostate cancer
Radiotherapy

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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Yang, L., Roberts, D., Takhar, M., Erho, N., Bibby, B. A. S., Thiruthaneeswaran, N., Bhandari, V., Cheng, W. C., Haider, S., McCorry, A. M. B., McArt, D., Jain, S., Alshalalfa, M., Ross, A., Schaffer, E., Den, R. B., Jeffrey Karnes, R., Klein, E., Hoskin, P. J., ... West, C. M. L. (2018). Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer. EBioMedicine, 31, 182-189. https://doi.org/10.1016/j.ebiom.2018.04.019

Yang, Lingjian ; Roberts, Darren ; Takhar, Mandeep ; Erho, Nicholas ; Bibby, Becky A.S. ; Thiruthaneeswaran, Niluja ; Bhandari, Vinayak ; Cheng, Wei Chen ; Haider, Syed ; McCorry, Amy M.B. ; McArt, Darragh ; Jain, Suneil ; Alshalalfa, Mohammed ; Ross, Ashley ; Schaffer, Edward ; Den, Robert B. ; Jeffrey Karnes, R. ; Klein, Eric ; Hoskin, Peter J. ; Freedland, Stephen J. ; Lamb, Alastair D. ; Neal, David E. ; Buffa, Francesca M. ; Bristow, Robert G. ; Boutros, Paul C. ; Davicioni, Elai ; Choudhury, Ananya ; West, Catharine M.L. / Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer. In: EBioMedicine. 2018 ; Vol. 31. pp. 182-189.

@article{9779fe40603c44759bbaf34c20ba1d95,

title = "Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer",

abstract = "Background: Hypoxia is associated with a poor prognosis in prostate cancer. This work aimed to derive and validate a hypoxia-related mRNA signature for localized prostate cancer. Method: Hypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signature. The signature was independently validated in eleven prostate cancer cohorts and a bladder cancer phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON). Results: A 28-gene signature was derived. Patients with high signature scores had poorer biochemical recurrence free survivals in six of eight independent cohorts of prostatectomy-treated patients (Log rank test P <.05), with borderline significances achieved in the other two (P <.1). The signature also predicted biochemical recurrence in patients receiving post-prostatectomy radiotherapy (n = 130, P =.007) or definitive radiotherapy alone (n = 248, P =.035). Lastly, the signature predicted metastasis events in a pooled cohort (n = 631, P =.002). Prognostic significance remained after adjusting for clinic-pathological factors and commercially available prognostic signatures. The signature predicted benefit from hypoxia-modifying therapy in bladder cancer patients (intervention-by-signature interaction test P =.0026), where carbogen and nicotinamide was associated with improved survival only in hypoxic tumours. Conclusion: A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients.",

keywords = "Gene expression signature, Hypoxia, Prognostic biomarker, Prostate cancer, Radiotherapy",

author = "Lingjian Yang and Darren Roberts and Mandeep Takhar and Nicholas Erho and Bibby, {Becky A.S.} and Niluja Thiruthaneeswaran and Vinayak Bhandari and Cheng, {Wei Chen} and Syed Haider and McCorry, {Amy M.B.} and Darragh McArt and Suneil Jain and Mohammed Alshalalfa and Ashley Ross and Edward Schaffer and Den, {Robert B.} and {Jeffrey Karnes}, R. and Eric Klein and Hoskin, {Peter J.} and Freedland, {Stephen J.} and Lamb, {Alastair D.} and Neal, {David E.} and Buffa, {Francesca M.} and Bristow, {Robert G.} and Boutros, {Paul C.} and Elai Davicioni and Ananya Choudhury and West, {Catharine M.L.}",

note = "Funding Information: Belfast-Manchester Movember Centre of Excellence (CE013_2-004), funded in partnership with Prostate Cancer UK (PG14 008 TR2). Cancer Research UK Major Centre funding. Cancer Research UK Manchester Institute Cancer Research Molecular Biology Core Facility and the University of Manchester Clinical Immune and Molecular Monitoring Laboratory for use of Good Clinical Practice facilities. Medical Research Council of the UK (grant G0801525). Cancer Research UK (grant C2094/A11365). Experimental Cancer Medicine Centre funding. CIHR New Investigator Award, TFRI New Investigator Award, CIHR Graduate Fellowship, Prostate Cancer Canada and the Movember Foundation (Grant RS2014-01). Cancer Research UK (grant 23969) and Oxford MRC/CRUK Institute. The work was supported by researchers at the NIHR Manchester Biomedical Research Centre. The funding sources have no roles in writing or decision or submit it for publication. Funding Information: MT, NE, MA, and ED are employees of GenomeDx Biosciences. RJK received research grant and royalties from GenomeDX . ",

year = "2018",

month = may,

doi = "10.1016/j.ebiom.2018.04.019",

language = "English (US)",

volume = "31",

pages = "182--189",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier BV",

}

Yang, L, Roberts, D, Takhar, M, Erho, N, Bibby, BAS, Thiruthaneeswaran, N, Bhandari, V, Cheng, WC, Haider, S, McCorry, AMB, McArt, D, Jain, S, Alshalalfa, M, Ross, A , Schaffer, E, Den, RB, Jeffrey Karnes, R, Klein, E, Hoskin, PJ, Freedland, SJ, Lamb, AD, Neal, DE, Buffa, FM, Bristow, RG, Boutros, PC, Davicioni, E, Choudhury, A & West, CML 2018, 'Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer', EBioMedicine, vol. 31, pp. 182-189. https://doi.org/10.1016/j.ebiom.2018.04.019

Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer. / Yang, Lingjian; Roberts, Darren; Takhar, Mandeep; Erho, Nicholas; Bibby, Becky A.S.; Thiruthaneeswaran, Niluja; Bhandari, Vinayak; Cheng, Wei Chen; Haider, Syed; McCorry, Amy M.B.; McArt, Darragh; Jain, Suneil; Alshalalfa, Mohammed; Ross, Ashley ; Schaffer, Edward; Den, Robert B.; Jeffrey Karnes, R.; Klein, Eric; Hoskin, Peter J.; Freedland, Stephen J.; Lamb, Alastair D.; Neal, David E.; Buffa, Francesca M.; Bristow, Robert G.; Boutros, Paul C.; Davicioni, Elai; Choudhury, Ananya; West, Catharine M.L.

In: EBioMedicine, Vol. 31, 05.2018, p. 182-189.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer

AU - Yang, Lingjian

AU - Roberts, Darren

AU - Takhar, Mandeep

AU - Erho, Nicholas

AU - Bibby, Becky A.S.

AU - Thiruthaneeswaran, Niluja

AU - Bhandari, Vinayak

AU - Cheng, Wei Chen

AU - Haider, Syed

AU - McCorry, Amy M.B.

AU - McArt, Darragh

AU - Jain, Suneil

AU - Alshalalfa, Mohammed

AU - Ross, Ashley

AU - Schaffer, Edward

AU - Den, Robert B.

AU - Jeffrey Karnes, R.

AU - Klein, Eric

AU - Hoskin, Peter J.

AU - Freedland, Stephen J.

AU - Lamb, Alastair D.

AU - Neal, David E.

AU - Buffa, Francesca M.

AU - Bristow, Robert G.

AU - Boutros, Paul C.

AU - Davicioni, Elai

AU - Choudhury, Ananya

AU - West, Catharine M.L.

N1 - Funding Information: Belfast-Manchester Movember Centre of Excellence (CE013_2-004), funded in partnership with Prostate Cancer UK (PG14 008 TR2). Cancer Research UK Major Centre funding. Cancer Research UK Manchester Institute Cancer Research Molecular Biology Core Facility and the University of Manchester Clinical Immune and Molecular Monitoring Laboratory for use of Good Clinical Practice facilities. Medical Research Council of the UK (grant G0801525). Cancer Research UK (grant C2094/A11365). Experimental Cancer Medicine Centre funding. CIHR New Investigator Award, TFRI New Investigator Award, CIHR Graduate Fellowship, Prostate Cancer Canada and the Movember Foundation (Grant RS2014-01). Cancer Research UK (grant 23969) and Oxford MRC/CRUK Institute. The work was supported by researchers at the NIHR Manchester Biomedical Research Centre. The funding sources have no roles in writing or decision or submit it for publication. Funding Information: MT, NE, MA, and ED are employees of GenomeDx Biosciences. RJK received research grant and royalties from GenomeDX .

PY - 2018/5

Y1 - 2018/5

N2 - Background: Hypoxia is associated with a poor prognosis in prostate cancer. This work aimed to derive and validate a hypoxia-related mRNA signature for localized prostate cancer. Method: Hypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signature. The signature was independently validated in eleven prostate cancer cohorts and a bladder cancer phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON). Results: A 28-gene signature was derived. Patients with high signature scores had poorer biochemical recurrence free survivals in six of eight independent cohorts of prostatectomy-treated patients (Log rank test P <.05), with borderline significances achieved in the other two (P <.1). The signature also predicted biochemical recurrence in patients receiving post-prostatectomy radiotherapy (n = 130, P =.007) or definitive radiotherapy alone (n = 248, P =.035). Lastly, the signature predicted metastasis events in a pooled cohort (n = 631, P =.002). Prognostic significance remained after adjusting for clinic-pathological factors and commercially available prognostic signatures. The signature predicted benefit from hypoxia-modifying therapy in bladder cancer patients (intervention-by-signature interaction test P =.0026), where carbogen and nicotinamide was associated with improved survival only in hypoxic tumours. Conclusion: A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients.

AB - Background: Hypoxia is associated with a poor prognosis in prostate cancer. This work aimed to derive and validate a hypoxia-related mRNA signature for localized prostate cancer. Method: Hypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signature. The signature was independently validated in eleven prostate cancer cohorts and a bladder cancer phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON). Results: A 28-gene signature was derived. Patients with high signature scores had poorer biochemical recurrence free survivals in six of eight independent cohorts of prostatectomy-treated patients (Log rank test P <.05), with borderline significances achieved in the other two (P <.1). The signature also predicted biochemical recurrence in patients receiving post-prostatectomy radiotherapy (n = 130, P =.007) or definitive radiotherapy alone (n = 248, P =.035). Lastly, the signature predicted metastasis events in a pooled cohort (n = 631, P =.002). Prognostic significance remained after adjusting for clinic-pathological factors and commercially available prognostic signatures. The signature predicted benefit from hypoxia-modifying therapy in bladder cancer patients (intervention-by-signature interaction test P =.0026), where carbogen and nicotinamide was associated with improved survival only in hypoxic tumours. Conclusion: A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients.

KW - Gene expression signature

KW - Hypoxia

KW - Prognostic biomarker

KW - Prostate cancer

KW - Radiotherapy

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DO - 10.1016/j.ebiom.2018.04.019

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JO - EBioMedicine

JF - EBioMedicine

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