The Senescence-SASP Landscape in Colon Adenocarcinoma: Prognostic and Therapeutic Implications

TL;DR

This study identifies a nine-gene signature linked to cellular senescence that predicts survival and treatment response in colon cancer patients.

Contribution

A novel nine-gene senescence-related signature (CSRS) was developed and validated for prognosis and immunotherapy response in colon adenocarcinoma.

Findings

The CSRS score, age, and TNM stage are independent prognostic indicators for overall survival in COAD patients.

CSRS-high patients show increased SASP and immune infiltration, while CSRS-low patients respond better to immunotherapy.

The CSRS genes may serve as biomarkers for prognosis and immunotherapeutic benefit in colon cancer.

Abstract

Cellular senescence, characterized by permanent cell cycle arrest, significantly influences cancer development, immune regulation, and progression. However, the precise mechanisms by which senescence contributes to colorectal cancer prognosis remain to be fully elucidated. By integrating expression profiles of senescence-related and prognostic genes in colon adenocarcinoma (COAD) patients, we formulated and confirmed a nine-gene cellular senescence-related signature (CSRS) that integrates senescence-associated and prognosis-predictive genes using data from the CellAge, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A cell senescence-related prognostic formula was developed as follows: CSRS = (CASP2 × 0.2098) + (CDKN2A × 0.1196) + (FOXD1 × 0.1472) + (ING5 × 0.3723) + (OXTR × 0.0786) + (PHGDH × 0.1408) + (SERPINE1 × 0.1127) + (SNAI1 × 0.1034) + (LIMK1 × 0.0747). In a multivariate Cox proportional hazards model, the CSRS score, age and TNM stage were all identified as significant independent indicators for overall survival, affirming their prognostic value in colorectal cancer. The CSRS-high group exhibited significantly up-regulated senescence-associated secretory phenotype (SASP) and immune cell infiltration, whereas the CSRS-low group showed an apparent better response to immune-checkpoint inhibitor therapy. Our findings suggest CSRS score and its constituent genes represent potential biomarkers for prognosis and immunotherapeutic benefit in COAD patients. Extending this nine-gene set into a broader senescence-associated panel should be a next step toward delivering truly individualized treatment plans.

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