High prevalence of DNA damage repair gene defects and TP53 alterations in men with treatment-naïve metastatic prostate cancer –Results from a prospective pilot study using a 37 gene panel

Nientiedt, Cathleen; Endris, Volker; Jenzer, Maximilian; Mansour, Josef; Sedehi, Nassim Tawanaie Pour; Pecqueux, Carine; Volckmar, Anna‐Lena; Leichsenring, Jonas; Neumann, Olaf; Kirchner, Martina; Hoveida, Shirin; Lantwin, Philippa; Kaltenecker, Katrin; Dieffenbacher, Svenja; Gasch, Claudia; Hofer, Luisa; Franke, Desiree; Tosev, Georgi; Görtz, Magdalena; Schütz, Viktoria; Radtke, Jan-Philipp; Nyarangi‐Dix, Joanne; Hatiboglu, Gencay; Simpfendörfer, Tobias; Schönberg, Gita; Isaac, S.; Teber, Doğu; Koerber, Stefan A.; Christofi, Georgia; Czink, Elena; Kreuter, Rebecca; Apostolidis, Leonidas; Kratochwil, Clemens; Giesel, Frederik L.; Haberkorn, Uwe; Debus, Jürgen; Sültmann, Holger; Zschäbitz, Stefanie; Jäger, Dirk; Duensing, Anette; Schirmacher, Peter; Grüllich, Carsten; Hohenfellner, Markus; Duensing, Stefan

doi:10.1016/j.urolonc.2020.03.001

Cited by 16 publications

(15 citation statements)

References 45 publications

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“…Remarkably, the rate of TP53 mutations in castration-naïve metastatic prostate cancer was between 28% and 36% and hence significantly higher than in primary prostate cancer (50,52,58) and only exceeded by mutation rates found in mCRPC. Analysis of 150 mCRPC samples showed a TP53 mutation rate of 53% (59).…”

Section: Tp53 Mutations In Prostate Cancermentioning

confidence: 90%

“…Initially, inactivation of TP53 has been suggested to be a late event during prostate cancer progression (46)(47)(48)(49). While it is now firmly established that mCRPC has the highest TP53 mutations rates (see below), there is emerging evidence that TP53 mutations can also be found at a relatively high frequency in primary, and, especially, in castration-naïve metastatic prostate cancer (50)(51)(52)(53)(54)(55)(56).…”

Section: Tp53 Mutations In Prostate Cancermentioning

confidence: 99%

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Revisiting the Role of p53 in Prostate Cancer

et al. 2021

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Mutations in the tumor suppressor gene TP53 are among the most common genetic aberrations in cancer. In prostate cancer, the role of mutant TP53 remains incompletely understood. Initially, mutations in TP53 were considered late events during malignant progression and associated with metastatic dissemination and castration resistance. However, recent studies report an inactivation of TP53 at an unexpectedly high frequency in primary as well as metastatic castration-naïve prostate cancer. In this chapter, we discuss the biology of p53, the relevance of TP53 mutations for prostate cancer progression and therapy

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Section: Tp53 Mutations In Prostate Cancermentioning

confidence: 90%

Section: Tp53 Mutations In Prostate Cancermentioning

confidence: 99%

Revisiting the Role of p53 in Prostate Cancer

et al. 2021

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“…In patients with mCRPC, the rate of somatic mutations was as high as of 23%‐33% 23‐25 . Remarkably, a similarly high prevalence of somatic mutations in DNA damage repair and checkpoint genes was found in treatment‐naïve metastatic prostate cancer 26 . Throughout all studies, the two genes most commonly affected by mutations are BRCA2 (7%‐14%) and ATM (6‐10%), of which 40%‐50% and 20%‐60%, respectively, are germline mutations 23‐25,27 …”

Section: Dna Damage Repair Gene Defects In Prostate Cancer Patientsmentioning

confidence: 98%

PARP inhibition in prostate cancer

Nientiedt

Duensing

Zschäbitz

et al. 2020

Genes Chromosomes & Cancer

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Defects in DNA damage repair genes are more common in prostate cancer than previously thought. These alterations provide an opportunity for precision oncology approaches and a number of studies have now shown that PARP inhibitors can have significant antitumor activity in men with DNA damage repair‐deficient metastatic castration‐resistant prostate cancer. This review summarizes the key clinical trials related to the use of PARP inhibitors in prostate cancer. Besides clinical outcomes, toxicity, and PARP inhibitor resistance, the role of different DNA repair genes in the response to PARP inhibition will be discussed.

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“…GO-RP uses not the only distance between enhancers and promoters, but also adjusts these scores and ranks elements based on the integration of ChIP-seq and expression data to accurately identify target genes. Notably, heterogeneous case met-ARBS regulate hallmarks of cancer pathways involved in cholesterol synthesis 43 , mTORC1 signaling 44 , androgen response, and WNT beta-catenin signaling 44 , whereas the P53 pathway, which is often inactivated in mPCa 10,45 , was activated by heterogeneous control met-ARBS. Moreover, individual metastasis-promoting genes such as proto-oncogene RET 46 or migration and invasiveness-related genes like CDH17, CDH18, ITGB5, and ITGB7, or osteoclast-promoting TF FOS2L 47 involved in the formation of bone metastases are found in this set and are regulated by heterogeneous met-ARBS detected in cases.…”

Section: Metastasis-associated Heterogeneous Arbs In Poor-outcome Pri...mentioning

confidence: 99%

Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential

et al. 2022

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Androgen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients’ outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact.

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High prevalence of DNA damage repair gene defects and TP53 alterations in men with treatment-naïve metastatic prostate cancer –Results from a prospective pilot study using a 37 gene panel

Cited by 16 publications

References 45 publications

Revisiting the Role of p53 in Prostate Cancer

Revisiting the Role of p53 in Prostate Cancer

PARP inhibition in prostate cancer

Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential

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