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A novel thinking: DDR axis refines the classification of ccRCC with distinctive prognosis, multi omics landscape and
Aimin Jiang1, Jiaao Song1, Xiao Fang2
1Department of Urology, Changhai Hospital, Navel Medical University (Second Military Medical University), Shanghai, China.
Background:
DNA damage response and repair (DDR) related signatures play an important role in maintaining genome stability and other biological processes. It also affects the occurrence, development, and treatment of cancer. However, in renal cell carcinoma (RCC), especially clear cell renal carcinoma (ccRCC), the potential association between DDR-related signatures and tumor heterogeneity and tumor microenvironment (TME) remains unclear.
Methods:
Utilizing unsupervised clustering algorithm, we divided RCC into two subgroups, DCS1 and DCS2, according to the differences in DDR gene expression, and compared the characteristics of the two subgroups through multiple dimensions.
Results:
Compared with DCS1, DCS2 patients have higher clinical stage/grade and worse prognosis, which may be related to active metabolic status and immunosuppression status. At the same time, the high mutation rate in DCS2 may also be an important reason for the prognosis. We also analyzed the sensitivity of the two subgroups to different therapeutic agents and established a subtypes' biomarkers-based prognostic system with good validation results to provide ideas for clinical diagnosis and treatment. Finally, we identified a pivotal role for DDX1 in the DDR gene set, which may serve as a future therapeutic target.
Conclusion:
This study showed that DDR has an important impact on the development and treatment of RCC. DCS2 subtypes have a poor prognosis, and more personalized treatment and follow-up programs may be needed. The assessment of DDR gene mutations in patients may be helpful for clinical decision-making. DDX1 may be one of the effective targets for RCC treatment in the future.
Insights
DNA damage response (DDR) signatures impact renal cell carcinoma (RCC) development and treatment. A specific subtype (DCS2) shows poor prognosis, highlighting the need for personalized therapies and potential DDX1 targeting.
Area of Science:
- Genomic stability and cancer biology
- Oncology and molecular diagnostics
- Renal cell carcinoma research
Background:
- DNA damage response (DDR) signatures are crucial for genome stability and cancer progression.
- The role of DDR signatures in renal cell carcinoma (RCC), particularly clear cell RCC (ccRCC), concerning tumor heterogeneity and microenvironment is not well understood.
- Understanding DDR's impact is vital for advancing cancer treatment strategies.
Purpose of the Study:
- To investigate the association between DDR-related gene expression and distinct subgroups within renal cell carcinoma (RCC).
- To characterize the clinical, molecular, and prognostic differences between identified RCC subgroups based on DDR signatures.
- To explore therapeutic sensitivities and identify potential biomarkers for improved RCC diagnosis and treatment.
Main Methods:
- Employed unsupervised clustering to classify RCC patients into two subgroups (DCS1 and DCS2) based on DDR gene expression.
- Conducted multi-dimensional comparative analysis of clinical stage, grade, prognosis, metabolic status, immune microenvironment, and mutation rates between the subgroups.
- Developed and validated a prognostic system utilizing subtype-specific biomarkers.
Main Results:
- RCC subgroup DCS2 exhibited significantly higher clinical stage/grade and poorer prognosis compared to DCS1, potentially linked to active metabolism and immunosuppression.
- A high mutation rate in the DCS2 subgroup was identified as a contributing factor to its worse prognosis.
- Differential sensitivity to therapeutic agents was observed between subgroups, and DDX1 was identified as a key DDR gene with potential as a therapeutic target.
Conclusions:
- DNA damage response (DDR) significantly influences the development and treatment outcomes of renal cell carcinoma (RCC).
- The DCS2 subgroup is associated with poor prognosis, necessitating personalized treatment and follow-up strategies.
- Assessing DDR gene mutations and targeting DDX1 may offer new avenues for clinical decision-making and effective RCC treatment.
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