Delineation of human prostate cancer evolution identifies chromothripsis as a polyclonal event and FKBP4 as a potential driver of castration resistance

Joël R. Federer-Gsponer, Cristina Quintavalle, David C. Müller, Tanja Dietsche, Valeria Perrina, Thomas Lorber, Darius Juskevicius, Elisabeth Lenkiewicz, Tobias Zellweger, Thomas Gasser, Michael Barrett, Cyrill A. Rentsch, Lukas Bubendorf, Christian Ruiz

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Understanding the evolutionary mechanisms and genomic events leading to castration-resistant (CR) prostate cancer (PC) is key to improve the outcome of this otherwise deadly disease. Here, we delineated the tumour history of seven patients progressing to castration resistance by analysing matched prostate cancer tissues before and after castration. We performed genomic profiling of DNA content-based flow-sorted populations in order to define the different evolutionary patterns. In one patient, we discovered that a catastrophic genomic event, known as chromothripsis, resulted in multiple CRPC tumour populations with distinct, potentially advantageous copy number aberrations, including an amplification of FK506 binding protein 4 (FKBP4, also known as FKBP52), a protein enhancing the transcriptional activity of androgen receptor signalling. Analysis of FKBP4 protein expression in more than 500 prostate cancer samples revealed increased expression in CRPC in comparison to hormone-naïve (HN) PC. Moreover, elevated FKBP4 expression was associated with poor survival of patients with HNPC. We propose FKBP4 amplification and overexpression as a selective advantage in the process of tumour evolution and as a potential mechanism associated with the development of CRPC. Furthermore, FKBP4 interaction with androgen receptor may provide a potential therapeutic target in PC.

Original languageEnglish (US)
Pages (from-to)74-84
Number of pages11
JournalJournal of Pathology
Volume245
Issue number1
DOIs
StatePublished - May 1 2018

Fingerprint

Castration
Prostatic Neoplasms
Androgen Receptors
Neoplasms
DNA Fingerprinting
Chromothripsis
tacrolimus binding protein 4
Population
Proteins
Hormones
Survival

Keywords

  • castration resistance
  • chromothripsis
  • evolution
  • FKBP4
  • FKBP52
  • hormone-naïve
  • prostate cancer
  • punctualism
  • survival

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Federer-Gsponer, J. R., Quintavalle, C., Müller, D. C., Dietsche, T., Perrina, V., Lorber, T., ... Ruiz, C. (2018). Delineation of human prostate cancer evolution identifies chromothripsis as a polyclonal event and FKBP4 as a potential driver of castration resistance. Journal of Pathology, 245(1), 74-84. https://doi.org/10.1002/path.5052

Delineation of human prostate cancer evolution identifies chromothripsis as a polyclonal event and FKBP4 as a potential driver of castration resistance. / Federer-Gsponer, Joël R.; Quintavalle, Cristina; Müller, David C.; Dietsche, Tanja; Perrina, Valeria; Lorber, Thomas; Juskevicius, Darius; Lenkiewicz, Elisabeth; Zellweger, Tobias; Gasser, Thomas; Barrett, Michael; Rentsch, Cyrill A.; Bubendorf, Lukas; Ruiz, Christian.

In: Journal of Pathology, Vol. 245, No. 1, 01.05.2018, p. 74-84.

Research output: Contribution to journalArticle

Federer-Gsponer, JR, Quintavalle, C, Müller, DC, Dietsche, T, Perrina, V, Lorber, T, Juskevicius, D, Lenkiewicz, E, Zellweger, T, Gasser, T, Barrett, M, Rentsch, CA, Bubendorf, L & Ruiz, C 2018, 'Delineation of human prostate cancer evolution identifies chromothripsis as a polyclonal event and FKBP4 as a potential driver of castration resistance', Journal of Pathology, vol. 245, no. 1, pp. 74-84. https://doi.org/10.1002/path.5052
Federer-Gsponer, Joël R. ; Quintavalle, Cristina ; Müller, David C. ; Dietsche, Tanja ; Perrina, Valeria ; Lorber, Thomas ; Juskevicius, Darius ; Lenkiewicz, Elisabeth ; Zellweger, Tobias ; Gasser, Thomas ; Barrett, Michael ; Rentsch, Cyrill A. ; Bubendorf, Lukas ; Ruiz, Christian. / Delineation of human prostate cancer evolution identifies chromothripsis as a polyclonal event and FKBP4 as a potential driver of castration resistance. In: Journal of Pathology. 2018 ; Vol. 245, No. 1. pp. 74-84.
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abstract = "Understanding the evolutionary mechanisms and genomic events leading to castration-resistant (CR) prostate cancer (PC) is key to improve the outcome of this otherwise deadly disease. Here, we delineated the tumour history of seven patients progressing to castration resistance by analysing matched prostate cancer tissues before and after castration. We performed genomic profiling of DNA content-based flow-sorted populations in order to define the different evolutionary patterns. In one patient, we discovered that a catastrophic genomic event, known as chromothripsis, resulted in multiple CRPC tumour populations with distinct, potentially advantageous copy number aberrations, including an amplification of FK506 binding protein 4 (FKBP4, also known as FKBP52), a protein enhancing the transcriptional activity of androgen receptor signalling. Analysis of FKBP4 protein expression in more than 500 prostate cancer samples revealed increased expression in CRPC in comparison to hormone-na{\"i}ve (HN) PC. Moreover, elevated FKBP4 expression was associated with poor survival of patients with HNPC. We propose FKBP4 amplification and overexpression as a selective advantage in the process of tumour evolution and as a potential mechanism associated with the development of CRPC. Furthermore, FKBP4 interaction with androgen receptor may provide a potential therapeutic target in PC.",
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