Mutations in TP53 or DNA damage repair genes define poor prognostic subgroups in primary prostate cancer

Nientiedt, Cathleen; Budczies, Jan; Endris, Volker; Kirchner, Martina; Schwab, Constantin; Jurcic, Christina; Behnisch, Rouven; Hoveida, Shirin; Lantwin, Philippa; Kaczorowski, Adam; Geisler, Christine; Dieffenbacher, Svenja; Falkenbach, Fabian; Franke, Desiree; Görtz, Magdalena; Heller, Martina; Himmelsbach, Ruth; Pecqueux, Carine; Rath, Mathias; Reimold, Philipp; Schütz, Viktoria; Šimunović, Iva; Walter, Elena; Hofer, Luisa; Gasch, Claudia; Schönberg, Gita; Pursche, Lars; Hatiboglu, Gencay; Nyarangi‐Dix, Joanne; Sültmann, Holger; Zschäbitz, Stefanie; Koerber, Stefan A.; Jäger, Dirk; Debus, Jürgen; Duensing, Anette; Schirmacher, Peter; Hohenfellner, Markus; Duensing, Stefan

doi:10.1016/j.urolonc.2021.06.024

Cited by 10 publications

(13 citation statements)

References 37 publications

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“…TP53 and SPOP mutations are the most common mutations in PCa. However, the prognostic role of TP53 and SPOP mutations in PCa has not been fully elucidated ( 20 ), which can be partly attributed to the difficulty of long follow-up, the difficulty in obtaining large sample sizes, unstandardized study approaches and the fact that some sequencing panels do not include TP53 and SPOP ( 9 ). Due to the good prognosis of localized PCa and the lack of large sample sequencing data, in this study, we focused on the effect of TP53 and SPOP mutations on OS in lethal metastatic PCa.…”

Section: Discussionmentioning

confidence: 99%

“…Since TP53 is widely mutated in human cancers, numerous studies have tried to answer the question of the impact of TP53 mutations on patient survival ( 6 – 8 ). For PCa, there are fewer relevant findings and a lack of large sample studies on the effect of TP53 mutations on prostate cancer survival ( 3 , 9 ). A recently published study on the prognostic impact of TP53 or DNA damage repair gene mutations concluded that TP53 mutations were an independent risk factor for PSA failure or PSA persistence and can be used to define a subgroup of patients in primary PCa ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

“…For PCa, there are fewer relevant findings and a lack of large sample studies on the effect of TP53 mutations on prostate cancer survival ( 3 , 9 ). A recently published study on the prognostic impact of TP53 or DNA damage repair gene mutations concluded that TP53 mutations were an independent risk factor for PSA failure or PSA persistence and can be used to define a subgroup of patients in primary PCa ( 9 ). Moreover, TP53 mutations were reported to be associated with metastasis and castration resistance ( 10 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive analysis of TP53 and SPOP mutations and their impact on survival in metastatic prostate cancer

et al. 2022

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BackgroundAlthough TP53 and SPOP are frequently mutated in metastatic prostate cancer (PCa), their prognostic value is ambiguous, and large sample studies are lacking, especially when they co-occur with other genetic alterations.MethodsGenomic data and patients’ clinical characteristics in PCa were downloaded from the cBioPortal database. We extensively analyzed other gene alterations in different mutation status of TP53 and SPOP. We further subdivided TP53 and SPOP mutation into subgroups based on different mutation status, and then evaluated the prognostic value. Two classification systems for TP53 survival analysis were used.ResultsA total of 2,172 patients with PCa were analyzed in our study, of which 1,799 were metastatic PCa patients. The mutual exclusivity analysis showed that TP53 and SPOP mutation has a strong mutual exclusion (p<0.001). In multivariable analysis, truncating TP53 mutations (HR=1.773, 95%CI:1.403-2.239, p<0.001) and other TP53 mutations(HR=1.555, 95%CI:1.267-1.908, p<0.001) were independent negative prognostic markers in metastatic PCa, whereas SPOP mutations(HR=0.592, 95%CI:0.427-0.819, p<0.001) were an independent prognostic factor for better prognosis. Mutations in TP53 were significantly associated with wild-type status for SPOP and CDK12, structural variants/fusions for TMPRSS2 and ERG, AR amplification and PTEN deletion (p<0.001). And truncating TP53 mutations have higher AR amplification rates than other TP53 mutations (p=0.022). Consistently, truncating TP53 mutations had a worse prognosis than other TP53 mutations (p<0.05). Then Kaplan-Meier survival curve showed that Co-occurring TP53 mutations in AR amplification or PTEN deletion tumors significantly reduced survival (p<0.05). Furthermore, those with SPOP-mutant tumors with co-occurring TP53 truncating mutations had shorter overall survival than those with SPOP-mutant tumors with wild-type or other TP53 mutations.ConclusionsThis study found that TP53 and SPOP mutations were mutually exclusive and both were independent prognostic markers for metastatic PCa. Genomic alteration and survival analysis revealed that TP53 and SPOP mutations represented distinct molecular subtypes. Our data suggest that molecular stratification on the basis of TP53 and SPOP mutation status should be implemented for metastatic PCa to optimize and modify clinical decision-making.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comprehensive analysis of TP53 and SPOP mutations and their impact on survival in metastatic prostate cancer

et al. 2022

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“…Lastly, tumors harboring certain alterations such as TP53 mutations and copy number gains seem to have increased ctDNA shedding, which may be due to increased metabolic activity or cellular turnover ( 71 ). In this regard, TP53 alterations have been suggested to be markers of aggressiveness and poor prognosis ( 78 ).…”

Section: Ctdna Levels In Different Types Of Cancermentioning

confidence: 99%

Circulating Tumor DNA as a Cancer Biomarker: An Overview of Biological Features and Factors That may Impact on ctDNA Analysis

et al. 2022

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Cancer cells release nucleic acids, freely or associated with other structures such as vesicles into body fluids, including blood. Among these nucleic acids, circulating tumor DNA (ctDNA) has emerged as a minimally invasive biomarker for tumor molecular profiling. However, certain biological characteristics of ctDNA are still unknown. Here, we provide an overview of the current knowledge about ctDNA biological features, including size and structure as well as the mechanisms of ctDNA shedding and clearance, and the physio-pathological factors that determine ctDNA levels. A better understanding of ctDNA biology is essential for the development of new methods that enable the analysis of ctDNA.

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“…Moreover, the gene TP53, which encodes the tumor-suppressor protein p53, is mutated in about 50% of malignancies, and p53 acts as a transcription factor to activate subsets of target genes which carry out cell fates, including DNA repair [48]. DNA damage-repair gene mutations are enriched in TP53 tumors, and TP53 or DNA damage-repair gene mutations are frequently detected in malignancies with high-risk features [49]. However, the aforementioned concerns require further investigation, the true potential of such a hypothesized oncogenetic cascade of full spike protein being in need of elucidation.…”

Section: Immunity After Sars-cov-2 Infection Versus Post Vaccinationmentioning

confidence: 99%

Ofeleein i mi Vlaptin—Volume II: Immunity Following Infection or mRNA Vaccination, Drug Therapies and Non-Pharmacological Management at Post-Two Years SARS-CoV-2 Pandemic

et al. 2022

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The persistence of the coronavirus disease 2019 (COVID-19) pandemic has triggered research into limiting transmission, morbidity and mortality, thus warranting a comprehensive approach to guide balanced healthcare policies with respect to people’s physical and mental health. The mainstay priority during COVID-19 is to achieve widespread immunity, which could be established through natural contact or vaccination. Deep knowledge of the immune response combined with recent specific data indicates the potential inferiority of induced immunity against infection. Moreover, the prevention of transmission has been founded on general non-pharmacological measures of protection, albeit debate exists considering their efficacy and, among other issues, their socio-psychological burden. The second line of defense is engaged after infection and is supported by a plethora of studied agents, such as antibiotics, steroids and non-steroid anti-inflammatory drugs, antiviral medications and other biological agents that have been proposed, though variability in terms of benefits and adverse events has not allowed distinct solutions, albeit certain treatments might have a role in prevention and/or treatment of the disease. This narrative review summarizes the existing literature on the advantages and weaknesses of current COVID-19 management measures, thus underlining the necessity of acting based on the classical principle of “ofeleein i mi vlaptin”, that is, to help or not to harm.

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Mutations in TP53 or DNA damage repair genes define poor prognostic subgroups in primary prostate cancer

Cited by 10 publications

References 37 publications

Comprehensive analysis of TP53 and SPOP mutations and their impact on survival in metastatic prostate cancer

Comprehensive analysis of TP53 and SPOP mutations and their impact on survival in metastatic prostate cancer

Circulating Tumor DNA as a Cancer Biomarker: An Overview of Biological Features and Factors That may Impact on ctDNA Analysis

Ofeleein i mi Vlaptin—Volume II: Immunity Following Infection or mRNA Vaccination, Drug Therapies and Non-Pharmacological Management at Post-Two Years SARS-CoV-2 Pandemic

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