SPCS, a Novel Classifier System Based on Senescence Axis Regulators Reveals Tumor Microenvironment Heterogeneity and Guides Frontline Therapy for Clear Cell Renal Carcinoma

Abstract

Rationale

The emerging evidence suggested that senescence regulator genes were involved in multi cancers, which may be utilized as new targets for cancers. However, the dysregulation and clinical impact of senescence regulator genes in clear cell renal cell cancer (ccRCC) were still in foggy.

Methods

Using multi-omics data from TCGA-KIRC and other datasets, we comprehensively investigated the function of senescence regulator genes in ccRCC. ccRCC patients could be remodeled into two significant different groups basing on senescence regulators expression: senescence-pattern cancer subtype1 (SPCS1) and subtype2 (SPCS2). We further explored clinical characteristics, functional analysis, tumor immune microenvironment, immunotherapy response, genomic mutation and drug sensitivity between the two subtypes. Besides, senescence-pattern related risk model was established to determine the patient's prognosis of ccRCC. Finally, the overview of MECP2 function was investigated in multi cancers.

Results

ccRCC patients could be divided into SPCS1 (normal aging group) and SPCS2 (Aging disorder group). The two subtypes showed significant different clinical characteristics and biological process in ccRCC. SPCS2, an aggressive subtype, comprised higher clinical stage and worse prognosis of ccRCC patients. SPCS2 subtype indicated activated oncogenic signaling pathway and metabolic signatures to prompt cancer expansion. SPCS2 subgroup owned immunocompromised status, which induced immune dysfunction and low ICI therapy response. The genome-copy numbers of SPCS2, including arm-gain and arm-loss was significantly more frequent than SPCS1. In addition, the two subtypes argue contrasting drug sensitivity profiles in clinical specimens and matched cell lines. Finally, we constructed a prognostic risk model consisted of each subtype's leading biomarkers, which exerted a satisfied performance for ccRCC patients.

Conclusion

Senescence regulator-related signature could modify functional pathways and tumor immune microenvironment by genome mutation and pathway interaction. Senescence regulator-related molecular subtype strengthen the understanding of ccRCC' characterization and guide clinical treatment. Targeting senescence regulators may be regard as a proper way in ccRCC. Micro-Abstract The emerging evidence suggested that senescence regulator genes might involve in the progression of clear cell renal cell cancer, while the details remain larger unknown. In this work, we comprehensively investigated the function of senescence regulator genes in ccRCC across multi omics and validated the findings with experiments. ccRCC patients could be divided into SPCS1 (normal aging group) and SPCS2 (Aging disorder group). SPCS2, an aggressive subtype, comprised higher clinical stage and worse prognosis, which indicated activated oncogenic signaling pathway and metabolic signatures to prompt cancer expansion. SPCS2 subgroup owned immunocompromised status, which induced immune dysfunction and low ICI therapy response. In conclusion, senescence regulator-related signature could modify functional pathways and tumor immune microenvironment by genome mutation and pathway interaction.