AbstractBackgroundLocalized prostate cancer (PCa) is a largely heterogeneous disease regarding its clinical behavior. Current risk stratification relies on clinicopathological parameters and distinguishing between indolent and aggressive cases remains challenging. To improve risk stratification, we aimed to identify new prognostic markers for PCa.MethodsWe performed an in silico analysis on publicly available PCa transcriptome datasets.

摘要背景局限性前列腺癌（PCa）是一种关于其临床行为的异质性疾病。目前的风险分层依赖于临床病理参数，区分惰性和侵袭性病例仍然具有挑战性。为了改善风险分层，我们旨在确定PCa的新预后标志物。方法我们对公开可用的PCa转录组数据集进行了计算机分析。

The top 20 prognostic genes were assessed in PCa tissue samples of our institutional cohort (n = 92) using the NanoString nCounter technology. The three most promising candidates were further assessed by immunohistochemistry (IHC) in an institutional (n = 121) and an independent validation cohort from the EMPACT consortium (n = 199).

使用NanoString nCounter技术在我们机构队列的PCa组织样本中评估了前20个预后基因（n=92）。通过免疫组织化学（IHC）在机构（n=121）和EMPACT财团的独立验证队列（n=199）中进一步评估了三个最有希望的候选人。

Cancer-specific survival (CSS) and progression-free survival (PFS) were used as endpoints.ResultsOur in silico analysis identified 113 prognostic genes. The prognostic values of seven of the top 20 genes were confirmed in our institutional radical prostatectomy (RPE) cohort. Low CENPO, P2RX5, ABCC5 as well as high ASF1B, NCAPH, UBE2C, and ZWINT gene expressions were associated with shorter CSS.

癌症特异性生存（CSS）和无进展生存（PFS）被用作终点。结果我们的计算机分析确定了113个预后基因。在我们的机构根治性前列腺切除术（RPE）队列中证实了前20个基因中的7个的预后价值。低CENPO，P2RX5，ABCC5以及高ASF1B，NCAPH，UBE2C和ZWINT基因表达与较短的CSS相关。

IHC analysis confirmed the significant associations between NCAPH and UBE2C staining and worse CSS. In the external validation cohort, higher NCAPH and ZWINT protein expressions were associated with shorter PFS. The combination of the newly identified tissue protein markers improved standard risk stratification models, such as D’Amico, CAPRA, and Cambridge prognostic groups.ConclusionsWe identified and validated high tissue levels of NCAPH, UBE2C, and ZWINT as novel prognostic risk factors in clinically localized PCa patients.

IHC分析证实了NCAPH和UBE2C染色与更差的CSS之间的显着关联。在外部验证队列中，较高的NCAPH和ZWINT蛋白表达与较短的PFS相关。。结论我们确定并验证了高组织水平的NCAPH，UBE2C和ZWINT是临床局限性PCa患者的新型预后危险因素。

The use of these markers can improve routinely used risk estimation models..

这些标记的使用可以改进常规使用的风险估计模型。。

IntroductionProstate cancer (PCa) is the most common cancer in males, with over 1.2 million new cases yearly worldwide, ranking fifth in cancer-related deaths [1]. The use of serum prostate-specific antigen (PSA) for early detection of PCa has resulted in a shift toward earlier diagnosis. However, it led to the detection of a high number of indolent PCa that do not necessitate active treatment and may remain asymptomatic throughout patient’s life [2].

简介前列腺癌（PCa）是男性中最常见的癌症，全球每年有120多万例新病例，在癌症相关死亡中排名第五（1）。使用血清前列腺特异性抗原（PSA）早期检测PCa已导致向早期诊断的转变。然而，它导致检测到大量无痛性PCa，不需要积极治疗，并且可能在患者一生中保持无症状（2）。

Approximately 30–45% of PCa patients detected through screening are overdiagnosed, leading to unnecessary treatments like radical prostatectomy (RPE) or radiation therapy (RT) [3]. To avoid the risk of overtreatment, current guidelines do not recommend wide-spread population-based PSA screening, though debate persists [4].

通过筛查发现的大约30-45%的PCa患者被过度诊断，导致不必要的治疗，如根治性前列腺切除术（RPE）或放射治疗（RT）。为了避免过度治疗的风险，目前的指南不建议广泛进行基于人群的PSA筛查，尽管争论仍然存在（4）。

Improved risk stratification is crucial for accurately distinguishing between low- and high-risk PCa cases, guiding treatment decisions towards active surveillance or treatment [5].The D’Amico risk stratification - based on PSA level, clinical stage, and biopsy Gleason score - stratifies patients into low-, intermediate-, and high-risk groups.

改善风险分层对于准确区分低风险和高风险PCa病例至关重要，指导治疗决策走向主动监测或治疗（5）。D'Amico风险分层-基于PSA水平，临床分期和活检Gleason评分-将患者分为低，中，高风险组。

The original, retrospective study revealed that patients with intermediate- and high-risk PCa benefit more from RPE or RT regarding 5-year biochemical recurrence (BCR)-free survival compared to implant with or without neoadjuvant androgen deprivation therapy. On the other hand, patients with low-risk PCa showed no significant differences in response to various therapies [6].

最初的回顾性研究显示，与有或没有新辅助雄激素剥夺治疗的植入物相比，中高危PCa患者在5年无生化复发（BCR）生存期方面从RPE或RT中获益更多。。

The prognostic relevance of D’Amico classification for the prediction of BCR, progression, overall-, and cancer-specific survival was subsequently confirmed in patients who underwent RPE [7]. More recently, the Cambridge Prognostic Groups (CPG), a five-strata model utilizing PSA at diagnosis, c.

随后在接受RPE的患者中证实了D'Amico分类对预测BCR，进展，总体和癌症特异性生存的预后相关性（7）。最近，剑桥预后小组（CPG）是一种在诊断时利用PSA的五层模型，c。

Data availability

数据可用性

Data sources and handling of the publicly available datasets used in this study are described in the Materials and Methods. Further details and other data that support the findings of this study are available from the corresponding authors upon request.

材料和方法中描述了本研究中使用的公开可用数据集的数据来源和处理。。

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Download referencesFundingThis project was supported by National Research, Development and Innovation Office of Hungary (PharmaLab, RRF-2.3.1-21-2022-00015 and TKP2021-NVA-15). Open access funding provided by Semmelweis University.Author informationAuthor notesThese authors contributed equally: Henning Reis, Tibor Szarvas.Authors and AffiliationsDepartment of Urology, University of Duisburg-Essen, Essen, GermanyCsilla Olah, Martin Spahn, Boris Hadaschik & Tibor SzarvasInstitute of Pathology, University Medicine Essen, University of Duisburg-Essen, Essen, GermanyFabian Mairinger, Michael Wessolly & Henning ReisDepartment of Urology, University Hospitals Leuven, Leuven, BelgiumSteven JoniauLindenhofspital, Bern, SwitzerlandMartin SpahnUrology Research Laboratory, Department for BioMedical Research, University of Bern, Bern, SwitzerlandMarianna Kruithof-de JulioDepartment of Urology, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandMarianna Kruithof-de JulioDepartment of Urology, Semmelweis University, Budapest, HungaryAron Soós, Péter Nyirády & Tibor SzarvasResearch Centre for Natural Sciences, Cancer Biomarker Research Group, Institute of Enzymology, Budapest, HungaryBalázs GyőrffyDepartment of Bioinformatics, Semmelweis University, Budapest, HungaryBalázs GyőrffyDr.

下载参考文献资助该项目得到了匈牙利国家研究，发展和创新办公室（PharmaLab，RRF-2.3.1-21-2022-00015和TKP2021-NVA-15）的支持。Semmelweis大学提供的开放获取资金。作者信息作者注意到这些作者做出了同样的贡献：Henning Reis，Tibor Szarvas。作者和附属机构杜伊斯堡-埃森大学泌尿外科，埃森，德国科西拉·奥拉，马丁·斯潘，鲍里斯·哈达斯奇克和蒂博尔·萨尔瓦什病理学研究所，杜伊斯堡-埃森大学，埃森，德国费边·梅林格，迈克尔·维索利和亨宁·赖斯，鲁汶大学医院泌尿外科，鲁汶，比利时史蒂文·乔尼奥林登·霍夫斯皮塔尔，伯尔尼，瑞士马丁·斯潘泌尿外科研究实验室，伯尔尼大学生物医学研究系，伯尔尼，瑞士伯尔尼Odepartment of Urology，Inselspital，Bern University Hospital，Bern，SwitzerlandMarianna Kruithof de JulioDepartment of Urology，Semmelweis University，Budapest，HungaryAron Soós，Péter Nyirády＆Tibor SzarvasResearch Center for Natural Sciences，Cancer Biomarker Research Group，Institute of Enzymology，Budapest，HungaryBalázs Győrffy HungaryBalázs GyőrffyDr，塞梅尔维斯大学生物信息学系，布达佩斯。

Senckenberg Institute of Pathology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, GermanyHenning ReisAuthorsCsilla OlahView author publicationsYou can also search for this author in.

森肯伯格病理学研究所，法兰克福大学医院，法兰克福歌德大学，法兰克福，德国Henning ReisAuthorsCsilla OlahView作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarFabian MairingerView author publicationsYou can also search for this author in

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PubMed Google ScholarContributionsCO: writing-original draft, data analysis, visualization. FM, MW and BG: methodology, data analysis. SJ, MS and MKJ resources, writing-review, and editing. BH: resources, supervision, writing-review, and editing. AS: writing-review, and editing.

PubMed Google ScholarContributionsCO：撰写原稿，数据分析，可视化。FM，MW和BG：方法论，数据分析。SJ，MS和MKJ资源，写作评论和编辑。BH：资源，监督，写作评论和编辑。AS：撰写评论和编辑。

PN: writing-review, and editing. HR: conceptualization, methodology, data analysis, visualization, writing-review, and editing. TS: conceptualization, methodology, funding acquisition, data analysis, writing-original draft. The work reported in the paper has been performed by the authors, unless clearly specified in the text.Corresponding authorCorrespondence to.

PN：撰写评论和编辑。人力资源：概念化，方法论，数据分析，可视化，写作评论和编辑。TS：概念化，方法论，资金获取，数据分析，撰写原稿。除非文中明确说明，否则本文报道的工作是由作者完成的。对应作者对应。

Tibor Szarvas.Ethics declarations

蒂博尔·萨尔瓦斯。道德宣言

Competing interests

BH: Advisory boards for Janssen, Bayer, ABX, Lightpoint, Amgen, MSD, Pfizer, Novartis. Invited speaker for Accord, Astellas, Janssen R&D. Honoraria from Uromed. Research funding from AAA/Novartis, Bristol Myers Squibb, and German Research Foundation. Leadership roles for DKG AUO and DGU. The authors declare no potential conflicts of interest with the present project and publication..

BH：杨森、拜耳、ABX、Lightpoint、安进、MSD、辉瑞、诺华的顾问委员会。雅阁特邀演讲者，阿斯特拉斯，扬森研发，Uromed荣誉。AAA/诺华，百时美施贵宝和德国研究基金会的研究资金。DKG AUO和DGU的领导角色。作者声明与本项目和出版物没有潜在的利益冲突。。

Ethics

伦理学

The study was performed in compliance with the Declaration of Helsinki and the institutional ethics committees approved the study protocol (21-9991-BO and KEK-BE128/2015).

这项研究是按照赫尔辛基宣言进行的，机构伦理委员会批准了研究方案（21-9991-BO和KEK-BE128/2015）。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationEnhancing Risk Stratification models in Localized Prostate Cancer by Novel Validated Tissue BiomarkersRights and permissions.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。补充信息通过新的经过验证的组织生物标志物权利和权限增强局部前列腺癌的风险分层模型。

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Reprints and permissionsAbout this articleCite this articleOlah, C., Mairinger, F., Wessolly, M. et al. Enhancing risk stratification models in localized prostate cancer by novel validated tissue biomarkers.

转载和许可本文引用本文Olah，C.，Mairinger，F.，Wessolly，M。等人通过新型验证的组织生物标志物增强局部前列腺癌的风险分层模型。

Prostate Cancer Prostatic Dis (2024). https://doi.org/10.1038/s41391-024-00918-9Download citationReceived: 13 May 2024Revised: 28 October 2024Accepted: 31 October 2024Published: 14 November 2024DOI: https://doi.org/10.1038/s41391-024-00918-9Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

前列腺癌前列腺疾病（2024）。https://doi.org/10.1038/s41391-024-00918-9Download引文收到日期：2024年5月13日修订日期：2024年10月28日接受日期：2024年10月31日发布日期：2024年11月14日OI：https://doi.org/10.1038/s41391-024-00918-9Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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