DNA Damage Response Pathway Alteration in Locally Advanced Clear-Cell Renal-Cell Carcinoma Is Associated With a Poor Outcome

Abstract

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.