DNA Copy Number Alterations Independently Predict for Biochemical Recurrence following Radiotherapy in Intermediate Risk Prostate Cancer

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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Somatic DNA copy number alterations and their potential clinical utility for predicting lethal prostate cancer

Asian Journal of Andrology ◽

10.1038/aja.2013.82 ◽

2013 ◽

Vol 15 (5) ◽

pp. 586-587

Author(s):

Wennuan Liu ◽

Li Wang ◽

Jianfeng Xu

Keyword(s):

Prostate Cancer ◽

Copy Number ◽

Clinical Utility ◽

Copy Number Alterations ◽

Dna Copy Number ◽

Potential Clinical Utility ◽

Dna Copy Number Alterations ◽

Lethal Prostate Cancer

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Feasibility and performance of a novel probe panel to detect somatic DNA copy number alterations in clinical specimens for predicting prostate cancer progression

The Prostate ◽

10.1002/pros.24057 ◽

2020 ◽

Vol 80 (14) ◽

pp. 1253-1262

Author(s):

Wennuan Liu ◽

Jun Hou ◽

Jacqueline Petkewicz ◽

Rong Na ◽

Chi‐Hsiung Wang ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Copy Number ◽

Prostate Cancer Progression ◽

Copy Number Alterations ◽

Dna Copy Number ◽

Clinical Specimens ◽

And Performance ◽

Dna Copy Number Alterations

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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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Faculty Opinions recommendation of Delayed radical prostatectomy for intermediate-risk prostate cancer is associated with biochemical recurrence: possible implications for active surveillance from the SEARCH database.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717992427.793473599 ◽

2013 ◽

Author(s):

Jean Pierre Droz ◽

Helen Boyle

Keyword(s):

Prostate Cancer ◽

Radical Prostatectomy ◽

Active Surveillance ◽

Biochemical Recurrence ◽

Intermediate Risk ◽

Risk Prostate Cancer

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Sex-dependent differences in DNA copy number alterations in hepatocellular carcinoma

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2012.00005 ◽

2012 ◽

Vol 32 (1) ◽

pp. 5-9 ◽

Cited By ~ 1

Author(s):

Bing-ji WEN ◽

Wen-ming CONG ◽

Ai-zhong WANG ◽

Song-qin HE ◽

Hong-mei JIANG ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Copy Number ◽

Copy Number Alterations ◽

Dna Copy Number ◽

Dna Copy Number Alterations

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From Benign Inflammatory Dermatosis to Cutaneous Lymphoma. DNA Copy Number Imbalances in Mycosis Fungoides versus Large Plaque Parapsoriasis

Medicina ◽

10.3390/medicina57050502 ◽

2021 ◽

Vol 57 (5) ◽

pp. 502

Author(s):

Georgiana Gug ◽

Caius Solovan

Keyword(s):

Mycosis Fungoides ◽

Copy Number ◽

Snp Array ◽

Chromosome 1 ◽

Copy Number Alterations ◽

Dna Copy Number ◽

Large Plaque ◽

Inflammatory Dermatosis ◽

Fresh Frozen ◽

Dna Copy Number Alterations

Background and Objectives: Mycosis fungoides (MF) and large plaque parapsoriasis (LPP) evolution provide intriguing data and are the cause of numerous debates. The diagnosis of MF and LPP is associated with confusion and imprecise definition. Copy number alterations (CNAs) may play an essential role in the genesis of cancer out of genes expression dysregulation. Objectives: Due to the heterogeneity of MF and LPP and the scarcity of the cases, there are an exceedingly small number of studies that have identified molecular changes in these pathologies. We aim to identify and compare DNA copy number alterations and gene expression changes between MF and LPP to highlight the similarities and the differences between these pathologies. Materials and Methods: The patients were prospectively selected from University Clinic of Dermatology and Venereology Timișoara, Romania. From fresh frozen skin biopsies, we extracted DNA using single nucleotide polymorphism (SNP) data. The use of SNP array for copy number profiling is a promising approach for genome-wide analysis. Results: After reviewing each group, we observed that the histograms generated for chromosome 1–22 were remarkably similar and had a lot of CNAs in common, but also significant differences were seen. Conclusions: This study took a step forward in finding out the differences and similarities between MF and LPP, for a more specific and implicitly correct approach of the case. The similarity between these two pathologies in terms of CNAs is striking, emphasizing once again the difficulty of approaching and differentiating them.

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