Prognostic value of copy-number alterations of the Cohesin complex in intermediate-risk prostate cancer recurrence.

49 Background: The Cohesin complex plays a critical role in mitotic progression and post-replicative DNA damage repair. It serves to bring together sister chromatids both in metaphase and in homologous recombination repair following ionizing radiation. The complex has also been shown to be phosphorylated in the ATM/BRCA1 pathway. The expression of various proteins in the complex are dysregulated in many cancers: breast, prostate, etc. Interestingly, in breast cancer cell lines, Cohesin is required for MYC activation in response to estrogen. Our study sought to correlate copy number alterations in this pivotal complex with biochemical relapse in prostate cancer patients. Methods: Our cohort consists of 284 patients with D’ Amico-classified intermediate-risk prostate cancer, treated with image-guided radiotherapy (IGRT, N = 143) or radical prostatectomy (RadP, N = 141). Pre-treatment biopsies and prostatectomy samples were analyzed using the Affymetrix Oncoscan array. The Phoenix and AUA criteria was used to define biochemical relapse for RadP and IGRT patients respectively. Results: Copy number alterations of RAD21, SMC1B, and STAG1 were observed in 18% (n = 52), 6.3% (n = 18), and 12% (n = 35) of the cohort respectively. They were predominantly losses in SMC1B, but gains in RAD21 and STAG1. All three genes in the Cohesin complex were associated with increased risk of biochemical relapse: RAD21 on chromosome 8 (HR = 1.93, 95% CI 1.23, 3.02, Wald’s p = 0.004), SMC1B on chromosome 22 (HR = 3.37, 95% CI 1.91, 5.94, Wald’s p < 10-4), and STAG1 on chromosome 3 (HR = 1.74, 95% CI 1.04, 2.89, Wald’s p < 0.05). However, when controlled for percent genome alteration and pre-treatment serum PSA levels, only copy number loss of SMC1B was a significant predictor of biochemical relapse (HR = 2.95, 95% CI 1.62, 5.38, Wald’s p < 10-3). Conclusions: We identified a novel association of copy-number alterations in members of the Cohesin complex with biochemical recurrence following radical prostatectomy or image-guided radiotherapy. This points to the central role of Cohesin in cell-cycle and DNA damage pathways promoting prostate cancer progression.

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Using NBN to predict biochemical relapse following image-guided radiotherapy (IGRT) for intermediate-risk prostate cancer (IR-PCa).

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.26 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 26-26

Author(s):

Alejandro Berlin ◽

Emilie Lalonde ◽

Gaetano Zafarana ◽

Jenna Sykes ◽

Varune Rohan Ramnarine ◽

...

Keyword(s):

Prostate Cancer ◽

Copy Number ◽

Prostate Cancer Cell ◽

Local Treatment ◽

Intermediate Risk ◽

Biochemical Relapse ◽

Image Guided Radiotherapy ◽

Image Guided ◽

Risk Prostate Cancer

26 Background: Despite the use of clinical prognostic factors, 20 to 40% of patients with intermediate-risk prostate cancer (IR-PCa) fail local treatment for unexplained reasons. Given that an accurate DNA damage response (DDR) may be associated with genetic instability and radioresponse, we investigated whether copy number alterations (CNAs) in DDR genes are predictive or prognostic following local treatment. Methods: Using array comparative genomic hybridization (aCGH), we characterized CNAs in biopsies derived from 126 IR-PCa pts. who underwent image-guided radiotherapy (IGRT). We studied the DDR-sensing genes: MRE11A, RAD50, NBN, ATM, and ATR. The IGRT cohort (median dose: 76.4Gy; median follow-up: 7.8yrs) was compared to a radical prostatectomy (RP) cohort (154 pts. from Memorial Sloan-Kettering Cancer Center database; median follow-up: 4.8yrs). CNAs were then tested for their independent prognostic capability using Kaplan-Meir method and Cox proportional hazard models. Results: In our IGRT cohort, m,ost frequent DDR gene CNAs were: NBN 20 of 126 (15.9%), ATR 11of 126 (8.7%), and ATM 7 of 126 (5.5%). NBN CNAs were mainly gains (19/20) and strongly correlated with increased NBN-mRNA abundance compared to NBN-neutral cases (p=0.016). CNAs in DDR genes were not associated with GS, prostate-specific antigen, or T-stage. Importantly, NBN gain ranked among the top 3.3% of all genes in terms of its strength of association with the percent of the genome altered (PGA). After adjusting for clinical factors in a multivariate model, NBN gain was a significant independent predictor of 5 years-biochemical relapse-free rate (bRFR) following IGRT (48.6% versus 78.8%; HR = 3.14, 95% CI: 1.42-6.94, p=0.004). No DDR CNA was prognostic in the RP cohort. Increased NBN mRNA expression correlated to radioresistance in vitro (i.e. clonogenic surviving fraction after 3Gy) in five prostate cancer cell lines (R2= 0.665). This relationship was not observed for any of the other DDR genes. Conclusions: NBN copy number gain or increased expression correlates with tumor genomic instability, decreased bRFR (IGRT- but not surgery-treated pts.) and intrinsic prostate cancer cell radioresistance. If validated in independent IGRT cohorts, NBN gain could be the first PCa predictive biomarker to facilitate local treatment decisions using precision medicine approaches.

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Copy number alterations of P53, RB1, and MDM2 as prognostic markers in intermediate-risk prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.117 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 117-117

Author(s):

Osman Mahamud ◽

Melvin Chua ◽

Emilie Lalonde ◽

Jonathan So ◽

Alan Dal Pra ◽

...

Keyword(s):

Prostate Cancer ◽

Radical Prostatectomy ◽

Copy Number ◽

Biochemical Failure ◽

Allelic Loss ◽

Intermediate Risk ◽

Copy Number Alterations ◽

Image Guided Radiotherapy ◽

Risk Prostate Cancer ◽

Prostate Cancers

117 Background: We interrogated copy number alternations (CNA) of p53, Rb1 and MDM2 as prognostic determinants of biochemical failure in localized intermediate-risk prostate cancer. Methods: Using Affymetrix Oncoscan array technology, we characterized copy number alterations (CNA) for 284 D’Amico-classified intermediate-risk prostate cancers. Of the 284 patients, 143 underwent image-guided radiotherapy (IGRT), while 141 underwent radical prostatectomy (RadP). Biochemical-relapse free survival (bRFS) was assessed as a clinical end-point, with biochemical failure defined using the Phoenix and AUA criteria for IGRT and RadP patients, respectively. Results: We observed allelic losses ofp53 and Rb1 in 23.9% (n = 68) and 31.0% (n = 88) and allelic gains of MDM2 in 3.17% (n = 9) in our cohort, respectively. 7.7% (n = 22), 1.1% (n = 3) and 0.4% (n = 1) of all cases exhibited concurrent losses of p53 and Rb1, p53 loss and MDM2 gain, and concurrent p53/Rb1 loss and MDM2 gain, respectively. Patients with allelic losses of p53, Rb1 and allelic gain of MDM2 loci exhibited increased percent genome aberration (PGA) (Mean 9.2 vs. 6.1 p < 0.001; 10.1 vs. 5.4 p < 0.001; 18.1 vs. 6.5 p < 0.001 respectively). Rb1 loss and MDM2 gain were not significant predictors of bRFS, independent of treatment modality. Allelic loss of p53 was predictive of poor bRFS in the RadP cohort (HR = 1.86, 95% CI 1.10-3.16, p = 0.022), but not for IGRT patients (HR = 1.16, 95% CI 0.63-2.12, p = 0.629). Additionally, patients in the RadP cohort with concurrent losses of p53 and Rb1 also had a higher likelihood of poorer bRFS (HR = 2.32, 95% CI 1.1-4.93, p = 0.029). On multivariate analysis, incorporating PGA and pre-treatment PSA, concurrent p53/Rb1 losses, but not single p53 loss, was prognostic for bRFS in patients who underwent RadP (p53/Rb1 losses, HR = 2.16, 95% CI 1.0-4.65, Wald's p = 0.05; p53loss, HR = 1.62, 95% CI 0.94-2.79, Wald's p = 0.08). Conclusions: In a cohort of men with intermediate-risk prostate cancers, we identified an unfavourable subgroup of patients harbouring concurrent copy number losses of p53 and Rb1 that was associated with an adverse prognosis of biochemical failure following radical prostatectomy.

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