Overexpression of thymidylate synthase (TYMS) is associated with aggressive tumor features and early PSA recurrence in prostate cancer

Burdelski, Christoph; Strauß, Christian; Tsourlakis, Maria Christina; Kluth, Martina; Hube‐Magg, Claudia; Melling, Nathaniel; Lebok, Patrick; Minner, Sarah; Koop, Christina; Graefen, Markus; Heinzer, Hans; Wittmer, Corinna; Krech, Till; Sauter, Guido; Wilczak, Waldemar; Simon, Ronald; Schlomm, Thorsten; Steurer, Stefan

doi:10.18632/oncotarget.3107

Cited by 49 publications

(41 citation statements)

References 55 publications

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“…Its expression is higher in neoplastic than in normal prostate epithelium and was shown to be tightly linked to high GS, pathological tumor stage and early PSA recurrence ( p < 0.0001) [27]. Noteworthy, TYMS protein is important target for 5-fluorouracil (5-FU) treatment, however this drug has only limited response rates in PCa [28].…”

Section: Discussionmentioning

confidence: 99%

Sarcosine Up-Regulates Expression of Genes Involved in Cell Cycle Progression of Metastatic Models of Prostate Cancer

et al. 2016

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The effects of sarcosine on the processes driving prostate cancer (PCa) development remain still unclear. Herein, we show that a supplementation of metastatic PCa cells (androgen independent PC-3 and androgen dependent LNCaP) with sarcosine stimulates cells proliferation in vitro. Similar stimulatory effects were observed also in PCa murine xenografts, in which sarcosine treatment induced a tumor growth and significantly reduced weight of treated mice (p < 0.05). Determination of sarcosine metabolism-related amino acids and enzymes within tumor mass revealed significantly increased glycine, serine and sarcosine concentrations after treatment accompanied with the increased amount of sarcosine dehydrogenase. In both tumor types, dimethylglycine and glycine-N-methyltransferase were affected slightly, only. To identify the effects of sarcosine treatment on the expression of genes involved in any aspect of cancer development, we further investigated expression profiles of excised tumors using cDNA electrochemical microarray followed by validation using the semi-quantitative PCR. We found 25 differentially expressed genes in PC-3, 32 in LNCaP tumors and 18 overlapping genes. Bioinformatical processing revealed strong sarcosine-related induction of genes involved particularly in a cell cycle progression. Our exploratory study demonstrates that sarcosine stimulates PCa metastatic cells irrespectively of androgen dependence. Overall, the obtained data provides valuable information towards understanding the role of sarcosine in PCa progression and adds another piece of puzzle into a picture of sarcosine oncometabolic potential.

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Section: Discussionmentioning

confidence: 99%

Sarcosine Up-Regulates Expression of Genes Involved in Cell Cycle Progression of Metastatic Models of Prostate Cancer

et al. 2016

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“…Similar observations were made for TYMS (thymidylate synthetase), which is involved in DNA replication and repair [25] and reported to correlate with worse outcome in PCa [29]. We observed that T2E-negative patients had significantly higher risk for short EFS with high TYMS expression -an effect that was absent in T2E-positive cases.…”

Section: Discussionsupporting

confidence: 88%

Biomarker-based outcome prediction in prostate adenocarcinoma depends on theTMPRSS2-ERGstatus

Gerke

Orth

Tolkach

et al. 2019

Preprint

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Background: Prostate adenocarcinoma (PCa) with/without the TMPRSS2-ERG (T2E)-fusion represent distinct molecular subtypes.Objective: To investigate gene-signatures associated with metastasis in T2E-positive and -negative PCa, and to identify and validate subtype-specific prognostic biomarkers.Design, setting and participants: Gene expression and clinicopathological data of two discovery PCa cohorts (total n=783) were separately analyzed regarding the T2E-status.Selected subtype-specific biomarkers were validated in two additional cohorts (total n=405).Outcome measurements and statistical analysis: From both discovery cohorts, we generated two gene lists ranked by their differential intratumoral expression in patients with/without metastases stratified by T2E-status, which were subjected to gene set enrichment and leading-edge analyses. The resulting top 20 gene-signatures of both gene lists associated with metastasis were analyzed for overlaps between T2E-positive and -negative cases. Genes shared by several functional gene-signatures were tested for their association with event-free survival using the Kaplan-Meier method in a validation cohort. Immunohistochemistry was performed in another validation cohort. Results and limitations:Metastatic T2E-positive and -negative PCa are characterized by different gene-signatures. Five genes (ASPN, BGN, COL1A1, RRM2 and TYMS) were identified whose high expression was significantly associated with worse outcome exclusively in T2E-negative PCa. This was validated in an independent cohort for all genes and additionally for RRM2 by immunohistochemistry in a separate validation cohort. No prognostic biomarkers were identified exclusively for T2E-positive tumors. Conclusions:Our study demonstrates that the prognostic value of biomarkers critically depends on the molecular subtype, i.e. the T2E-status, which should be considered when screening for and applying novel prognostic biomarkers for outcome prediction in PCa.

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“…Similar observations were made for TYMS (thymidylate synthetase), which is involved in DNA replication and repair 30 and reported to correlate with worse outcomes in PCa. 34 We observed that T2E-negative patients had significantly higher risk for short EFS with high TYMS expression-an effect that was absent in T2E-positive cases.…”

Section: Discussionmentioning

confidence: 59%

Integrative clinical transcriptome analysis reveals TMPRSS2‐ERG dependency of prognostic biomarkers in prostate adenocarcinoma

Gerke¹,

Orth²,

Tolkach

et al. 2019

Intl Journal of Cancer

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In prostate adenocarcinoma (PCa), distinction between indolent and aggressive disease is challenging. Around 50% of PCa are characterized by TMPRSS2-ERG (T2E)-fusion oncoproteins defining two molecular subtypes (T2E-positive/negative). However, current prognostic tests do not differ between both molecular subtypes, which might affect outcome prediction. To investigate gene-signatures associated with metastasis in T2E-positive and T2E-negative PCa independently, we integrated tumor transcriptomes and clinicopathological data of two cohorts (total n = 783), and analyzed metastasis-associated genesignatures regarding the T2E-status. Here, we show that the prognostic value of biomarkers in PCa critically depends on the Additional Supporting Information may be found in the online version of this article.

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Overexpression of thymidylate synthase (TYMS) is associated with aggressive tumor features and early PSA recurrence in prostate cancer

Cited by 49 publications

References 55 publications

Sarcosine Up-Regulates Expression of Genes Involved in Cell Cycle Progression of Metastatic Models of Prostate Cancer

Sarcosine Up-Regulates Expression of Genes Involved in Cell Cycle Progression of Metastatic Models of Prostate Cancer

Biomarker-based outcome prediction in prostate adenocarcinoma depends on theTMPRSS2-ERGstatus

Integrative clinical transcriptome analysis reveals TMPRSS2‐ERG dependency of prognostic biomarkers in prostate adenocarcinoma

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