A novel thinking: DDR axis refines the classification of ccRCC with distinctive prognosis, multi omics landscape and management strategy

Abstract

BackgroundDNA 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.MethodsUtilizing 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.ResultsCompared 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.ConclusionThis 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.

Clinical Significance and Expression Pattern of RIP5 and VGLL4 in Clear Cell Renal Cell Carcinoma Patients Treated with Sunitinib

“…VGLL4 is downregulated in ccRCC [56]. VGLL4 is also associated with metastasis and recurrence in ccRCC [59]. In our study, we found that in the renal cortex and medulla of normal control kidneys, VGLL4 is expressed in tubules with strong focal expression in epithelial cells.…”

“…Our results at the VGLL4 protein level are in accordance with the results on the transcriptomic level. Another two papers that investigated VGLL4 in ccRCC were performed on transcriptomic data and mRNA data in available open access databases [56,59]. Their findings also demonstrated worse overall survival in patients with low VGLL4 expression.…”

Identification and verification of prognostic cancer subtype based on multi-omics analysis for kidney renal papillary cell carcinoma

“…Mutation profiles of KIRP were acquired and we compared and visualized the difference of mutation among the MOCS subtypes utilizing Maftools package of R ( 47 ). We applied the Maftools function to analyze the oncogenic pathway and mutually exclusive or coexisting mutations ( 48 ). The loss and gain in genomic level was evaluated by GISTIC 2.0 algorithm ( 49 ).…”

Histone methyltransferase SETD2: An epigenetic driver in clear cell renal cell carcinoma

“…Compared to introns and non-transcribed regions, H3K36me3 and MutS are more enriched in exons as well as active transcriptional regions and transcriptionally protect against actively transcribed genes ( 74 ). Recent studies suggest that targeting DDR is feasible to achieve immunotherapy in ccRCC ( 75 , 76 ) ( Figure 3 ).…”