Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy

Gaetano Zafarana, Adrian Ishkanian, Chad A. Malloff, Jennifer A. Locke, Jenna Sykes, John Thoms, Wan L. Lam, Jeremy A. Squire, Maisa Yoshimoto, Varune Rohan Ramnarine, Alice Meng, Omar Ahmed, Igor Jurisca, Michael Milosevic, Melania Pintilie, Theo Van Der Kwast, Robert G. Bristow

Research output: Contribution to journalArticle

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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. Cancer 2012. © 2012 American Cancer Society. Array-based comparative genomic hybridization analysis of frozen, pretreatment biopsies from 126 patients with intermediate-risk prostate cancer demonstrates that copy number alterations in c-MYC and PTEN genes are prognostic for relapse following modern era image-guided radiotherapy.

Original languageEnglish (US)
Pages (from-to)4053-4062
Number of pages10
JournalCancer
Volume118
Issue number16
DOIs
StatePublished - Aug 15 2012
Externally publishedYes

Fingerprint

Prostatic Neoplasms
Radiotherapy
Recurrence
Comparative Genomic Hybridization
Image-Guided Radiotherapy
Loss of Heterozygosity
Biopsy
Prostaglandins A
Genes
Therapeutics
Neoplasms
Neoplasm Grading
Genomic Instability
Prostatectomy
Fluorescence In Situ Hybridization
Neoplasm Metastasis
DNA

Keywords

  • c-MYC
  • comparative genomic hybridization
  • genetic instability
  • Gleason score
  • prostate cancer
  • prostate-specific antigen
  • radiotherapy
  • T category

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Zafarana, G., Ishkanian, A., Malloff, C. A., Locke, J. A., Sykes, J., Thoms, J., ... Bristow, R. G. (2012). Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy. Cancer, 118(16), 4053-4062. https://doi.org/10.1002/cncr.26729

Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy. / Zafarana, Gaetano; Ishkanian, Adrian; Malloff, Chad A.; Locke, Jennifer A.; Sykes, Jenna; Thoms, John; Lam, Wan L.; Squire, Jeremy A.; Yoshimoto, Maisa; Ramnarine, Varune Rohan; Meng, Alice; Ahmed, Omar; Jurisca, Igor; Milosevic, Michael; Pintilie, Melania; Van Der Kwast, Theo; Bristow, Robert G.

In: Cancer, Vol. 118, No. 16, 15.08.2012, p. 4053-4062.

Research output: Contribution to journalArticle

Zafarana, G, Ishkanian, A, Malloff, CA, Locke, JA, Sykes, J, Thoms, J, Lam, WL, Squire, JA, Yoshimoto, M, Ramnarine, VR, Meng, A, Ahmed, O, Jurisca, I, Milosevic, M, Pintilie, M, Van Der Kwast, T & Bristow, RG 2012, 'Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy', Cancer, vol. 118, no. 16, pp. 4053-4062. https://doi.org/10.1002/cncr.26729
Zafarana G, Ishkanian A, Malloff CA, Locke JA, Sykes J, Thoms J et al. Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy. Cancer. 2012 Aug 15;118(16):4053-4062. https://doi.org/10.1002/cncr.26729
Zafarana, Gaetano ; Ishkanian, Adrian ; Malloff, Chad A. ; Locke, Jennifer A. ; Sykes, Jenna ; Thoms, John ; Lam, Wan L. ; Squire, Jeremy A. ; Yoshimoto, Maisa ; Ramnarine, Varune Rohan ; Meng, Alice ; Ahmed, Omar ; Jurisca, Igor ; Milosevic, Michael ; Pintilie, Melania ; Van Der Kwast, Theo ; Bristow, Robert G. / Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy. In: Cancer. 2012 ; Vol. 118, No. 16. pp. 4053-4062.
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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. Cancer 2012. {\circledC} 2012 American Cancer Society. Array-based comparative genomic hybridization analysis of frozen, pretreatment biopsies from 126 patients with intermediate-risk prostate cancer demonstrates that copy number alterations in c-MYC and PTEN genes are prognostic for relapse following modern era image-guided radiotherapy.",
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AU - Thoms, John

AU - Lam, Wan L.

AU - Squire, Jeremy A.

AU - Yoshimoto, Maisa

AU - Ramnarine, Varune Rohan

AU - Meng, Alice

AU - Ahmed, Omar

AU - Jurisca, Igor

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KW - prostate-specific antigen

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