title: Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy.
abstract: Despite the use of PSA, Gleason score, and T-category as prognosticators in intermediate-risk prostate cancer, 20-40% of patients will fail local therapy. In order to optimize treatment approaches for intermediate-risk patients, additional genetic prognosticators are needed. Previous reports using array comparative genomic hybridization (aCGH) in radical prostatectomy cohorts suggested a combination of allelic loss of the PTEN gene on 10q and allelic gain of the c-MYC gene on 8q were associated with metastatic disease. We tested whether copy number alterations (CNAs) in PTEN (allelic loss) and c-MYC (allelic gain) were associated with biochemical relapse following modern-era, image-guided radiotherapy (mean dose 76.4 Gy). We used aCGH analyses validated by fluorescence in-situ hybridization (FISH) of DNA was derived from frozen, pre-treatment biopsies in 126 intermediate-risk prostate cancer patients. Patients whose tumors had CNAs in both PTEN and c-MYC had significantly increased genetic instability (percent genome alteration; PGA) compared to tumors with normal PTEN and c-MYC status (p < 0.0001). We demonstrate that c-MYC gain alone, or combined c-MYC gain and PTEN loss, were increasingly prognostic for relapse on multivariable analyses (hazard ratios (HR) of 2.58/p = 0.005 and 3.21/p = 0.0004; respectively). Triaging patients by the use of CNAs within pre-treatment biopsies may allow for better use of systemic therapies to target sub-clinical metastases or locally recurrent disease and improve clinical outcomes.
authors.affiliation: Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Zafarana
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ishkanian
authors.forename: Chad A
authors.initials: CA
authors.lastname: Malloff
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Locke
authors.forename: Jenna
authors.initials: J
authors.lastname: Sykes
authors.forename: John
authors.initials: J
authors.lastname: Thoms
authors.forename: Wan L
authors.initials: WL
authors.lastname: Lam
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Squire
authors.forename: Maisa
authors.initials: M
authors.lastname: Yoshimoto
authors.forename: Varune Rohan
authors.initials: VR
authors.lastname: Ramnarine
authors.forename: Alice
authors.initials: A
authors.lastname: Meng
authors.forename: Omar
authors.initials: O
authors.lastname: Ahmed
authors.forename: Igor
authors.initials: I
authors.lastname: Jurisica
authors.forename: Igor
authors.initials: I
authors.lastname: Jurisca
authors.forename: Michael
authors.initials: M
authors.lastname: Milosevic
authors.forename: Melania
authors.initials: M
authors.lastname: Pintilie
authors.forename: Theo
authors.initials: T
authors.lastname: van der Kwast
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
mesh_terms: D000328:Adult; D056915:DNA Copy Number Variations; D016259:Genes, myc; D042822:Genomic Instability; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D061089:Radiotherapy, Image-Guided; D012008:Recurrence
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human