| Title: |
Patient-Level DNA Damage and Repair Pathway Profiles and Prognosis After Prostatectomy for High-Risk Prostate Cancer. |
| Authors: |
Evans, JR; Zhao, SG; Chang, SL; Tomlins, SA; Erho, N; Sboner, A; Schiewer, MJ; Spratt, DE; Kothari, V; Klein, EA; Den, RB; Dicker, AP; Karnes, RJ; Yu, X; Nguyen, PL; Rubin, MA; de Bono, J; Knudsen, KE; Davicioni, E; Feng, FY |
| Contributors: |
De Bono, Johann |
| Publication Year: |
2017 |
| Collection: |
The Institute of Cancer Research (ICR): Publications Repository |
| Subject Terms: |
Humans; Prostatic Neoplasms; DNA Damage; Prognosis; Prostatectomy; Oligonucleotide Array Sequence Analysis; Proportional Hazards Models; Risk Factors; Case-Control Studies; Retrospective Studies; Cohort Studies; Gene Expression Profiling; DNA Repair; Aged; Middle Aged; Male; Kaplan-Meier Estimate; Transcriptome; Biomarkers; Tumor |
| Description: |
Importance A substantial number of patients diagnosed with high-risk prostate cancer are at risk for metastatic progression after primary treatment. Better biomarkers are needed to identify patients at the highest risk to guide therapy intensification.Objective To create a DNA damage and repair (DDR) pathway profiling method for use as a prognostic signature biomarker in high-risk prostate cancer.Design, setting, and participants A cohort of 1090 patients with high-risk prostate cancer who underwent prostatectomy and were treated at 3 different academic institutions were divided into a training cohort (n = 545) and 3 pooled validation cohorts (n = 232, 130, and 183) assembled for case-control or case-cohort studies. Profiling of 9 DDR pathways using 17 gene sets for GSEA (Gene Set Enrichment Analysis) of high-density microarray gene expression data from formalin-fixed paraffin-embedded prostatectomy samples with median 10.3 years follow-up was performed. Prognostic signature development from DDR pathway profiles was studied, and DDR pathway gene mutation in published cohorts was analyzed.Main outcomes and measures Biochemical recurrence-free, metastasis-free, and overall survival.Results Across the training cohort and pooled validation cohorts, 1090 men were studied; mean (SD) age at diagnosis was 65.3 (6.4) years. We found that there are distinct clusters of DDR pathways within the cohort, and DDR pathway enrichment is only weakly correlated with clinical variables such as age (Spearman ρ [ρ], range, -0.07 to 0.24), Gleason score (ρ, range, 0.03 to 0.20), prostate-specific antigen level (ρ, range, -0.07 to 0.10), while 13 of 17 DDR gene sets are strongly correlated with androgen receptor pathway enrichment (ρ, range, 0.33 to 0.82). In published cohorts, DDR pathway genes are rarely mutated. A DDR pathway profile prognostic signature built in the training cohort was significantly associated with biochemical recurrence-free, metastasis-free, and overall survival in the pooled validation cohorts independent of ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
Print; 480; application/pdf |
| Language: |
English |
| ISSN: |
2374-2445; 2374-2437 |
| Relation: |
JAMA oncology, 2016, 2 (4), pp. 471 - 480; https://repository.icr.ac.uk/handle/internal/416 |
| DOI: |
10.1001/jamaoncol.2015.4955 |
| Availability: |
https://doi.org/10.1001/jamaoncol.2015.4955; https://repository.icr.ac.uk/handle/internal/416 |
| Rights: |
https://www.rioxx.net/licenses/all-rights-reserved |
| Accession Number: |
edsbas.520A8519 |
| Database: |
BASE |