DNA damage response alterations in clear cell renal cell carcinoma: clinical, molecular, and prognostic implications
Abstract 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, molecu...
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | European Journal of Medical Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40001-024-01678-x |
| _version_ | 1797275331117187072 |
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| author | Xiao Jing Xiangcheng Qin Hao Liu Huanhuan Liu Huina Wang Jiayue Qin Yanui Zhang Shanbo Cao Xiaodong Fan |
| author_facet | Xiao Jing Xiangcheng Qin Hao Liu Huanhuan Liu Huina Wang Jiayue Qin Yanui Zhang Shanbo Cao Xiaodong Fan |
| author_sort | Xiao Jing |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-07T15:12:47Z |
| format | Article |
| id | doaj.art-2412f0ddee8e42009ad02f0fe2ecef41 |
| institution | Directory Open Access Journal |
| issn | 2047-783X |
| language | English |
| last_indexed | 2024-03-07T15:12:47Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | European Journal of Medical Research |
| spelling | doaj.art-2412f0ddee8e42009ad02f0fe2ecef412024-03-05T18:04:17ZengBMCEuropean Journal of Medical Research2047-783X2024-02-0129111210.1186/s40001-024-01678-xDNA damage response alterations in clear cell renal cell carcinoma: clinical, molecular, and prognostic implicationsXiao Jing0Xiangcheng Qin1Hao Liu2Huanhuan Liu3Huina Wang4Jiayue Qin5Yanui Zhang6Shanbo Cao7Xiaodong Fan8Department of Urology, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Urology, Ningbo Urology and Nephrology HospitalDepartment of Urology, The Second Affiliated Hospital of Zhejiang University School of MedicineAcornmed Biotechnology Co., Ltd.Acornmed Biotechnology Co., Ltd.Acornmed Biotechnology Co., Ltd.Acornmed Biotechnology Co., Ltd.Acornmed Biotechnology Co., Ltd.Department of Urology, Ningbo Urology and Nephrology HospitalAbstract 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.https://doi.org/10.1186/s40001-024-01678-xClear cell renal cell carcinoma (ccRCC)DNA damage repair (DDR)PrognosisTumor microenvironmentTumor mutational burden (TMB) |
| spellingShingle | Xiao Jing Xiangcheng Qin Hao Liu Huanhuan Liu Huina Wang Jiayue Qin Yanui Zhang Shanbo Cao Xiaodong Fan DNA damage response alterations in clear cell renal cell carcinoma: clinical, molecular, and prognostic implications European Journal of Medical Research Clear cell renal cell carcinoma (ccRCC) DNA damage repair (DDR) Prognosis Tumor microenvironment Tumor mutational burden (TMB) |
| title | DNA damage response alterations in clear cell renal cell carcinoma: clinical, molecular, and prognostic implications |
| title_full | DNA damage response alterations in clear cell renal cell carcinoma: clinical, molecular, and prognostic implications |
| title_fullStr | DNA damage response alterations in clear cell renal cell carcinoma: clinical, molecular, and prognostic implications |
| title_full_unstemmed | DNA damage response alterations in clear cell renal cell carcinoma: clinical, molecular, and prognostic implications |
| title_short | DNA damage response alterations in clear cell renal cell carcinoma: clinical, molecular, and prognostic implications |
| title_sort | dna damage response alterations in clear cell renal cell carcinoma clinical molecular and prognostic implications |
| topic | Clear cell renal cell carcinoma (ccRCC) DNA damage repair (DDR) Prognosis Tumor microenvironment Tumor mutational burden (TMB) |
| url | https://doi.org/10.1186/s40001-024-01678-x |
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