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Background <p>Disulfidptosis and cuproptosis are recently identified forms of regulated cell death whose component genes may harbor prognostic information in oral squamous cell carcinoma (OSCC). However, no validated multi-gene prognostic signature derived from these pathways has been established.</p> Methods <p>Differentially expressed genes from two GEO discovery cohorts (GSE30784 and GSE37991) were intersected with 28 disulfidptosis- and cuproptosis-related genes. A LASSO-Cox model was developed in a TCGA oral HNSC training cohort (<i>n</i> = 268) and validated in GSE41613 (<i>n</i> = 97), GSE65858 (<i>n</i> = 270), and GSE42743 (<i>n</i> = 55). An extended clinical-genomic model incorporating age, AJCC stage, histological grade, alcohol use, radiation, and chemotherapy was evaluated in a complete-case subcohort (<i>n</i> = 212). Single-cell RNA-seq data (GSE103322; 5,902 cells) were analyzed to characterize hub gene expression across cell types. Hub gene expression was validated by qRT-PCR and ELISA in OSCC cell lines.</p> Results <p>A four-gene signature (CDKN2A, FLNA, GLS, TLN1) was identified. The risk score was an independent prognostic factor (HR = 1.36 per SD, 95% CI: 1.08–1.72, <i>P</i> = 0.009) after adjustment for six clinical covariates. The extended combined model achieved a C-index of 0.669 and a 5-year AUC of 0.805, outperforming the extended clinical model (C-index 0.650; 5-year AUC 0.722) and gene-only model (C-index 0.563; 5-year AUC 0.684). The signature achieved significance in GSE41613 (<i>P</i> = 0.046, HR = 1.81) and GSE65858 (<i>P</i> = 0.0013, HR = 1.99), with a concordant trend in GSE42743 (<i>P</i> = 0.079, HR = 2.10). Single-cell analysis showed that CDKN2A was preferentially expressed in malignant cells, while FLNA and TLN1 were enriched in fibroblasts, consistent with ECM-mediated tumor-stromal crosstalk. CellChat revealed that high-activity malignant cells exhibited enhanced LAMININ, COLLAGEN, and THBS signaling. qRT-PCR and ELISA confirmed upregulation of all four hub genes in CAL-27 and SCC-9 cells (<i>P</i> &lt; 0.01).</p> Conclusions <p>A four-gene prognostic signature derived from disulfidptosis- and cuproptosis-related genes provides independent prognostic value in OSCC and improves stratification when combined with standard clinical variables.</p>

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Development and validation of a four-gene prognostic signature derived from disulfidptosis- and cuproptosis-related genes in oral squamous cell carcinoma

  • 期刊论文

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  • 发表日期：

    2026年6月19日

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  • Yao Yao,
  • Xiaoshan Li,
  • Ziyan Pang,
  • Wenming Kang,
  • Liqiang Gong,
  • Qi Zhou,
  • Chen Mao

摘要

Background

Disulfidptosis and cuproptosis are recently identified forms of regulated cell death whose component genes may harbor prognostic information in oral squamous cell carcinoma (OSCC). However, no validated multi-gene prognostic signature derived from these pathways has been established.

Methods

Differentially expressed genes from two GEO discovery cohorts (GSE30784 and GSE37991) were intersected with 28 disulfidptosis- and cuproptosis-related genes. A LASSO-Cox model was developed in a TCGA oral HNSC training cohort (n = 268) and validated in GSE41613 (n = 97), GSE65858 (n = 270), and GSE42743 (n = 55). An extended clinical-genomic model incorporating age, AJCC stage, histological grade, alcohol use, radiation, and chemotherapy was evaluated in a complete-case subcohort (n = 212). Single-cell RNA-seq data (GSE103322; 5,902 cells) were analyzed to characterize hub gene expression across cell types. Hub gene expression was validated by qRT-PCR and ELISA in OSCC cell lines.

Results

A four-gene signature (CDKN2A, FLNA, GLS, TLN1) was identified. The risk score was an independent prognostic factor (HR = 1.36 per SD, 95% CI: 1.08–1.72, P = 0.009) after adjustment for six clinical covariates. The extended combined model achieved a C-index of 0.669 and a 5-year AUC of 0.805, outperforming the extended clinical model (C-index 0.650; 5-year AUC 0.722) and gene-only model (C-index 0.563; 5-year AUC 0.684). The signature achieved significance in GSE41613 (P = 0.046, HR = 1.81) and GSE65858 (P = 0.0013, HR = 1.99), with a concordant trend in GSE42743 (P = 0.079, HR = 2.10). Single-cell analysis showed that CDKN2A was preferentially expressed in malignant cells, while FLNA and TLN1 were enriched in fibroblasts, consistent with ECM-mediated tumor-stromal crosstalk. CellChat revealed that high-activity malignant cells exhibited enhanced LAMININ, COLLAGEN, and THBS signaling. qRT-PCR and ELISA confirmed upregulation of all four hub genes in CAL-27 and SCC-9 cells (P < 0.01).

Conclusions

A four-gene prognostic signature derived from disulfidptosis- and cuproptosis-related genes provides independent prognostic value in OSCC and improves stratification when combined with standard clinical variables.