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Published on: February 8, 2020
DNA Damage Response Pathway Alteration in Locally Advanced Clear-Cell Renal-Cell Carcinoma Is Associated With a Poor
Joon Chae Na1, Naoya Nagaya2, Koon Ho Rha1
1Department of Urology, Yonsei University College of Medicine, Urological Science Institute, Seoul, Korea.
Background:
Advanced clear-cell renal-cell carcinoma (ccRCC), which is the most common subtype of kidney cancer, is considered to be lethal despite recent advancements in therapeutic agents. The benefit of adjuvant or neoadjuvant therapy with currently available agents remains controversial. We investigated the clinical implications of DNA damage response (DDR) pathway for locally advanced ccRCC.
Patients And Methods:
Localized ccRCC cases were selected from the Provisional TCGA (The Cancer Genome Atlas) database. Presence of mutation or copy-number alteration of DDR pathway-related genes were evaluated. Disease-free survival and overall survival according to disease progression were evaluated.
Results:
From TCGA database, 312 cases were identified of a localized ccRCC with full data on mutation and copy-number alteration. Alteration in the DDR pathway was present in 25.0% of cases. Female subjects were more likely to have alterations in the DDR pathway (34.6% vs. 48.7%, P = .026). DDR pathway alteration was associated with decreased disease-free survival in cases of locally advanced T3-4 disease (median, 123.7 vs. 23.0 months, T3 and T4 disease, P = .031). The association was more prominent in cases of T3a disease (normal group median not reached, altered group median 17.7 months, P < .001). DDR pathway alteration was an independent factor predicting a shorter disease-free survival on Cox regression analysis (odds ratio = 4.41; 95% confidence interval, 1.47∼13.28; P = .008).
Conclusion:
Alteration in the DDR pathway was associated with increased recurrence in locally advanced ccRCC, and investigation of therapeutic agents targeting the DDR pathway for this population should be considered.
Insights
Alterations in the DNA damage response (DDR) pathway are common in advanced clear-cell renal-cell carcinoma (ccRCC). These DDR pathway alterations predict increased recurrence and poorer survival in ccRCC patients.
Area of Science:
- Oncology
- Genetics
- Cancer Biology
Background:
- Advanced clear-cell renal-cell carcinoma (ccRCC) remains lethal despite therapeutic advancements.
- The efficacy of current adjuvant or neoadjuvant therapies for ccRCC is debated.
- This study explores the clinical significance of the DNA damage response (DDR) pathway in locally advanced ccRCC.
Purpose of the Study:
- To investigate the clinical implications of DNA damage response (DDR) pathway alterations in locally advanced clear-cell renal-cell carcinoma (ccRCC).
- To assess the association between DDR pathway alterations and disease-free and overall survival in ccRCC patients.
Main Methods:
- Utilized data from 312 localized ccRCC cases from The Cancer Genome Atlas (TCGA) database.
- Evaluated mutations and copy-number alterations in DDR pathway-related genes.
- Analyzed disease-free survival and overall survival in relation to disease progression and DDR pathway status.
Main Results:
- DDR pathway alterations were identified in 25.0% of ccRCC cases.
- DDR pathway alterations were more frequent in female subjects (34.6% vs. 48.7%, P = .026).
- Alterations in the DDR pathway significantly decreased disease-free survival in locally advanced T3-4 disease (median 23.0 months vs. 123.7 months, P = .031), particularly in T3a disease (P < .001).
- DDR pathway alteration was an independent predictor of shorter disease-free survival (OR = 4.41, P = .008).
Conclusions:
- Alterations in the DNA damage response (DDR) pathway correlate with increased recurrence in locally advanced ccRCC.
- Targeting the DDR pathway presents a potential therapeutic strategy for locally advanced ccRCC patients.
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