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Updated: Jul 4, 2025
Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
DNA damage response alterations in clear cell renal cell carcinoma: clinical, molecular, and prognostic implications
Xiao Jing1, Xiangcheng Qin2, Hao Liu1
1Department of Urology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Background:
DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic responses. Nonetheless, the characteristics and significance of DDR alterations in clear cell renal cell carcinoma (ccRCC) remain undefined. This study aimed to explore the predictive role, molecular mechanism, and tumor immune profile of DDR genes in ccRCC.
Methods:
We prospectively sequenced 757 tumors and matched blood DNA samples from Chinese patients with ccRCC using next-generation sequencing (NGS) and analyzed data from 537 patients from The Cancer Genome Atlas (TCGA). A comprehensive analysis was performed.
Results:
Fifty-two percent of Chinese patients with ccRCC harbored DDR gene mutations and 57% of TCGA patients. The immunotherapy treatment prognosis of patients with DDR gene mutations was superior to that of patients without DDR gene mutations (p = 0.047). DDR gene mutations were associated with more gene mutations and a higher tumor mutation load (TMB, p < 0.001). Moreover, patients with DDR gene mutations have a distinct mutational signature compared with those with wild-type DDR. Furthermore, the DDR-mut group had elevated neoantigen load (including single-nucleotide variants (SNV) and indel neoantigen load, p = 0.037 and p = 0.002, respectively), TCR Shannon (p = 0.025), and neutrophils (p = 0.010). DDR gene mutations exhibited a distinct immune profile with significantly higher expression levels of TNFSF9, CD70, ICAM1, and indoleamine-2,3-dioxygenase (IDO) and lower expression levels of VTCN1 and IL12A.
Conclusions:
Our data suggest that the detection of somatic mutations in DDR genes can predict the efficacy of immunotherapy in patients with ccRCC. Furthermore, we revealed the unique molecular and immune mechanisms underlying ccRCC with DDR gene mutations.
Insights
Mutations in DNA damage repair (DDR) genes are common in clear cell renal cell carcinoma (ccRCC) and predict better immunotherapy outcomes. These mutations also influence the tumor
Area of Science:
- Oncology
- Genetics
- Immunotherapy
Background:
- DNA damage repair (DDR) pathways are crucial in cancer development and treatment response.
- The role of DDR alterations in clear cell renal cell carcinoma (ccRCC) is not well understood.
- This study investigates DDR genes in ccRCC to understand their predictive value, molecular mechanisms, and immune profile.
Purpose of the Study:
- To explore the predictive role of DDR gene alterations in ccRCC.
- To elucidate the molecular mechanisms associated with DDR mutations in ccRCC.
- To characterize the tumor immune profile in ccRCC patients with DDR gene mutations.
Main Methods:
- Prospective sequencing of 757 ccRCC tumors and matched blood DNA from Chinese patients.
- Analysis of data from 537 ccRCC patients from The Cancer Genome Atlas (TCGA).
- Comprehensive genomic and immune profiling analysis.
Main Results:
- DDR gene mutations were found in 52% of Chinese ccRCC patients and 57% of TCGA patients.
- Patients with DDR mutations showed superior immunotherapy prognosis and higher tumor mutation burden (TMB).
- DDR mutations were associated with increased neoantigen load, distinct mutational signatures, and altered immune cell infiltration and gene expression.
Conclusions:
- Somatic mutations in DDR genes can predict immunotherapy efficacy in ccRCC patients.
- DDR gene mutations are linked to unique molecular and immune characteristics in ccRCC.
- Identifying DDR alterations offers insights into ccRCC pathogenesis and therapeutic strategies.
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