Clinical and genomic analysis of metastatic prostate cancer progression with a background of postoperative biochemical recurrence

Mohammed Alshalalfa, Anamaria Crisan, Ismael A. Vergara, Mercedeh Ghadessi, Christine Buerki, Nicholas Erho, Kasra Yousefi, Thomas Sierocinski, Zaid Haddad, Peter C. Black, Robert Jeffrey Karnes, Robert Brian Jenkins, Elai Davicioni

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Objective To better characterize the genomics of patients with biochemical recurrence (BCR) who have metastatic disease progression in order to improve treatment decisions for prostate cancer. Methods The expression profiles of three clinical outcome groups after radical prostatectomy (RP) were compared: those with no evidence of disease (NED; n = 108); those with BCR (rise in prostate-specific antigen [PSA] level without metastasis; n = 163); and those with metastasis (n = 192). The patients were profiled using Human Exon 1.0 ST microarrays, and outcomes were supported by a median 18 years of follow-up. A metastasis signature was defined and verified in an independent RP cohort to ensure the robustness of the signature. Furthermore, bioinformatics characterization of the signature was conducted to decipher its biology. Results Minimal gene expression differences were observed between adjuvant treatment-naïve patients in the NED group and patients without metastasis in the BCR group. More than 95% of the differentially expressed genes (metastasis signature) were found in comparisons between primary tumours of metastasis patients and the two other outcome groups. The metastasis signature was validated in an independent cohort and was significantly associated with cell cycle genes, ubiquitin-mediated proteolysis, DNA repair, androgen, G-protein coupled and NOTCH signal transduction pathways. Conclusion This study shows that metastasis development after BCR is associated with a distinct transcriptional programme that can be detected in the primary tumour. Patients with NED and BCR have highly similar transcriptional profiles, suggesting that measurement of PSA on its own is a poor surrogate for lethal disease. Use of genomic testing in patients undergoing RP with an initial rise in PSA level may be useful to improve secondary therapy decision-making.

Original languageEnglish (US)
Pages (from-to)556-567
Number of pages12
JournalBJU International
Volume116
Issue number4
DOIs
StatePublished - Oct 1 2015

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Prostatic Neoplasms
Neoplasm Metastasis
Recurrence
Prostate-Specific Antigen
Prostatectomy
cdc Genes
Ubiquitin
Genomics
Computational Biology
GTP-Binding Proteins
DNA Repair
Androgens
Proteolysis
Disease Progression
Exons
Signal Transduction
Neoplasms
Decision Making
Therapeutics
Gene Expression

Keywords

  • biochemical recurrence
  • gene expression
  • gene functional analysis
  • metastasis
  • prostate cancer

ASJC Scopus subject areas

  • Urology

Cite this

Alshalalfa, M., Crisan, A., Vergara, I. A., Ghadessi, M., Buerki, C., Erho, N., ... Davicioni, E. (2015). Clinical and genomic analysis of metastatic prostate cancer progression with a background of postoperative biochemical recurrence. BJU International, 116(4), 556-567. https://doi.org/10.1111/bju.13013

Clinical and genomic analysis of metastatic prostate cancer progression with a background of postoperative biochemical recurrence. / Alshalalfa, Mohammed; Crisan, Anamaria; Vergara, Ismael A.; Ghadessi, Mercedeh; Buerki, Christine; Erho, Nicholas; Yousefi, Kasra; Sierocinski, Thomas; Haddad, Zaid; Black, Peter C.; Karnes, Robert Jeffrey; Jenkins, Robert Brian; Davicioni, Elai.

In: BJU International, Vol. 116, No. 4, 01.10.2015, p. 556-567.

Research output: Contribution to journalArticle

Alshalalfa, M, Crisan, A, Vergara, IA, Ghadessi, M, Buerki, C, Erho, N, Yousefi, K, Sierocinski, T, Haddad, Z, Black, PC, Karnes, RJ, Jenkins, RB & Davicioni, E 2015, 'Clinical and genomic analysis of metastatic prostate cancer progression with a background of postoperative biochemical recurrence', BJU International, vol. 116, no. 4, pp. 556-567. https://doi.org/10.1111/bju.13013
Alshalalfa, Mohammed ; Crisan, Anamaria ; Vergara, Ismael A. ; Ghadessi, Mercedeh ; Buerki, Christine ; Erho, Nicholas ; Yousefi, Kasra ; Sierocinski, Thomas ; Haddad, Zaid ; Black, Peter C. ; Karnes, Robert Jeffrey ; Jenkins, Robert Brian ; Davicioni, Elai. / Clinical and genomic analysis of metastatic prostate cancer progression with a background of postoperative biochemical recurrence. In: BJU International. 2015 ; Vol. 116, No. 4. pp. 556-567.
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abstract = "Objective To better characterize the genomics of patients with biochemical recurrence (BCR) who have metastatic disease progression in order to improve treatment decisions for prostate cancer. Methods The expression profiles of three clinical outcome groups after radical prostatectomy (RP) were compared: those with no evidence of disease (NED; n = 108); those with BCR (rise in prostate-specific antigen [PSA] level without metastasis; n = 163); and those with metastasis (n = 192). The patients were profiled using Human Exon 1.0 ST microarrays, and outcomes were supported by a median 18 years of follow-up. A metastasis signature was defined and verified in an independent RP cohort to ensure the robustness of the signature. Furthermore, bioinformatics characterization of the signature was conducted to decipher its biology. Results Minimal gene expression differences were observed between adjuvant treatment-na{\"i}ve patients in the NED group and patients without metastasis in the BCR group. More than 95{\%} of the differentially expressed genes (metastasis signature) were found in comparisons between primary tumours of metastasis patients and the two other outcome groups. The metastasis signature was validated in an independent cohort and was significantly associated with cell cycle genes, ubiquitin-mediated proteolysis, DNA repair, androgen, G-protein coupled and NOTCH signal transduction pathways. Conclusion This study shows that metastasis development after BCR is associated with a distinct transcriptional programme that can be detected in the primary tumour. Patients with NED and BCR have highly similar transcriptional profiles, suggesting that measurement of PSA on its own is a poor surrogate for lethal disease. Use of genomic testing in patients undergoing RP with an initial rise in PSA level may be useful to improve secondary therapy decision-making.",
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T1 - Clinical and genomic analysis of metastatic prostate cancer progression with a background of postoperative biochemical recurrence

AU - Alshalalfa, Mohammed

AU - Crisan, Anamaria

AU - Vergara, Ismael A.

AU - Ghadessi, Mercedeh

AU - Buerki, Christine

AU - Erho, Nicholas

AU - Yousefi, Kasra

AU - Sierocinski, Thomas

AU - Haddad, Zaid

AU - Black, Peter C.

AU - Karnes, Robert Jeffrey

AU - Jenkins, Robert Brian

AU - Davicioni, Elai

PY - 2015/10/1

Y1 - 2015/10/1

N2 - Objective To better characterize the genomics of patients with biochemical recurrence (BCR) who have metastatic disease progression in order to improve treatment decisions for prostate cancer. Methods The expression profiles of three clinical outcome groups after radical prostatectomy (RP) were compared: those with no evidence of disease (NED; n = 108); those with BCR (rise in prostate-specific antigen [PSA] level without metastasis; n = 163); and those with metastasis (n = 192). The patients were profiled using Human Exon 1.0 ST microarrays, and outcomes were supported by a median 18 years of follow-up. A metastasis signature was defined and verified in an independent RP cohort to ensure the robustness of the signature. Furthermore, bioinformatics characterization of the signature was conducted to decipher its biology. Results Minimal gene expression differences were observed between adjuvant treatment-naïve patients in the NED group and patients without metastasis in the BCR group. More than 95% of the differentially expressed genes (metastasis signature) were found in comparisons between primary tumours of metastasis patients and the two other outcome groups. The metastasis signature was validated in an independent cohort and was significantly associated with cell cycle genes, ubiquitin-mediated proteolysis, DNA repair, androgen, G-protein coupled and NOTCH signal transduction pathways. Conclusion This study shows that metastasis development after BCR is associated with a distinct transcriptional programme that can be detected in the primary tumour. Patients with NED and BCR have highly similar transcriptional profiles, suggesting that measurement of PSA on its own is a poor surrogate for lethal disease. Use of genomic testing in patients undergoing RP with an initial rise in PSA level may be useful to improve secondary therapy decision-making.

AB - Objective To better characterize the genomics of patients with biochemical recurrence (BCR) who have metastatic disease progression in order to improve treatment decisions for prostate cancer. Methods The expression profiles of three clinical outcome groups after radical prostatectomy (RP) were compared: those with no evidence of disease (NED; n = 108); those with BCR (rise in prostate-specific antigen [PSA] level without metastasis; n = 163); and those with metastasis (n = 192). The patients were profiled using Human Exon 1.0 ST microarrays, and outcomes were supported by a median 18 years of follow-up. A metastasis signature was defined and verified in an independent RP cohort to ensure the robustness of the signature. Furthermore, bioinformatics characterization of the signature was conducted to decipher its biology. Results Minimal gene expression differences were observed between adjuvant treatment-naïve patients in the NED group and patients without metastasis in the BCR group. More than 95% of the differentially expressed genes (metastasis signature) were found in comparisons between primary tumours of metastasis patients and the two other outcome groups. The metastasis signature was validated in an independent cohort and was significantly associated with cell cycle genes, ubiquitin-mediated proteolysis, DNA repair, androgen, G-protein coupled and NOTCH signal transduction pathways. Conclusion This study shows that metastasis development after BCR is associated with a distinct transcriptional programme that can be detected in the primary tumour. Patients with NED and BCR have highly similar transcriptional profiles, suggesting that measurement of PSA on its own is a poor surrogate for lethal disease. Use of genomic testing in patients undergoing RP with an initial rise in PSA level may be useful to improve secondary therapy decision-making.

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KW - gene expression

KW - gene functional analysis

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