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Background <p>Prostate adenocarcinoma (PRAD) has substantial recurrence after primary treatment, and reliable prediction is clinically needed. We integrated clinical, genomic, and transcriptomic data to identify recurrence-associated genes, characterize their tumor microenvironmental context, and develop a prognostic model.</p> Methods <p>Gene expression and clinical data were obtained from TCGA (training; <i>n</i> = 145) and the GEO dataset GSE54460 (validation; <i>n</i> = 106). Single-cell RNA-seq data were analyzed to resolve gene expression across cell types. Immune infiltration was estimated using ssGSEA and the ESTIMATE algorithm, and cell–cell communication was assessed with CellChat. Recurrence-associated genes were identified by univariate Cox regression, and a LASSO Cox model was used to construct and externally validate the risk score.</p> Results <p>Pathological T stage, N stage, Gleason score, and TP53 mutation were linked to higher recurrence risk. We identified six risk genes (<i>AMH</i>,<i> CRYBA2</i>,<i> CTHRC1</i>,<i> EFNA2</i>,<i> BMP6</i>,<i> ARHGDIG</i>) and two protective genes (<i>CKMT2</i>,<i> IP6K3</i>) and built a risk-score model that discriminated against PFS in the training and validation cohorts. Single-cell analysis localized <i>CTHRC1</i> predominantly to a fibroblast subpopulation characterized by upregulated midkine (MDK) signaling and extensive intercellular communication. Drug–gene correlation screening nominated decitabine, tegafur, calusterone, EMD-1204831, and ARQ-680; expression of several risk genes positively correlated with CTLA4, suggesting testable sensitivity to checkpoint blockade.</p> Conclusions <p>Clinical variables together with transcriptomic features—particularly a CTHRC1-high fibroblast program—associate with PRAD recurrence. The externally validated risk score and the stromal context of CTHRC1/MDK provide testable avenues for prognosis and therapeutic exploration.</p>

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Fibroblast-associated CTHRC1 as a key indicator of recurrence risk in prostate cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月14日

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  • Yuan Ma,
  • Gaoteng Lin,
  • Keruo Wang,
  • Zihao Liu,
  • Yuan Shao,
  • Wenyue Yu,
  • Xiaoyi Zhao,
  • Dan Yu,
  • Fangfang Zhan,
  • Xinghang Wang,
  • Shida Duan,
  • KeFei Duan

摘要

Background

Prostate adenocarcinoma (PRAD) has substantial recurrence after primary treatment, and reliable prediction is clinically needed. We integrated clinical, genomic, and transcriptomic data to identify recurrence-associated genes, characterize their tumor microenvironmental context, and develop a prognostic model.

Methods

Gene expression and clinical data were obtained from TCGA (training; n = 145) and the GEO dataset GSE54460 (validation; n = 106). Single-cell RNA-seq data were analyzed to resolve gene expression across cell types. Immune infiltration was estimated using ssGSEA and the ESTIMATE algorithm, and cell–cell communication was assessed with CellChat. Recurrence-associated genes were identified by univariate Cox regression, and a LASSO Cox model was used to construct and externally validate the risk score.

Results

Pathological T stage, N stage, Gleason score, and TP53 mutation were linked to higher recurrence risk. We identified six risk genes (AMH, CRYBA2, CTHRC1, EFNA2, BMP6, ARHGDIG) and two protective genes (CKMT2, IP6K3) and built a risk-score model that discriminated against PFS in the training and validation cohorts. Single-cell analysis localized CTHRC1 predominantly to a fibroblast subpopulation characterized by upregulated midkine (MDK) signaling and extensive intercellular communication. Drug–gene correlation screening nominated decitabine, tegafur, calusterone, EMD-1204831, and ARQ-680; expression of several risk genes positively correlated with CTLA4, suggesting testable sensitivity to checkpoint blockade.

Conclusions

Clinical variables together with transcriptomic features—particularly a CTHRC1-high fibroblast program—associate with PRAD recurrence. The externally validated risk score and the stromal context of CTHRC1/MDK provide testable avenues for prognosis and therapeutic exploration.