{
  "abstract": "Background DNA damage repair (DDR) genes are a class of genes that play a significant role in the occurrence and drug resistance of tumor cells. Current research has shown that certain DDR genes are related to the efficacy of immunotherapy. However, the association between alterations in the DDR gene family in tumors and the response to immune checkpoint inhibitors still requires further investigation, for that prior studies have focused on either an individual gene or a predefined set of genes. Herein, this study aimed to evaluate the predictive potential of DDR gene mutations for treatment responses to immune checkpoint inhibitors across various cancers. By developing and validating DDR gene signatures, the research sought to establish biomarkers that could optimize therapeutic outcomes in immunotherapy.Methods The study utilized data from multiple independent cohorts, including patients treated with ICIs, collected via whole-exome sequencing and targeted sequencing. The analysis incorporated DDR gene mutations, tumor mutational burden, and clinical data. The research applied machine learning algorithms to create DDR-based biomarker signatures and validated their predictive accuracy across different cancer types. Furthermore, we incorporated single-nucleus RNA sequencing (snRNA-seq) and ATAC-seq data from a clear cell renal cell carcinoma cohort to investigate transcriptomic and epigenetic alterations associated with DDR mutations.Results Analyzing over 10,953 patient revealed that DDR gene mutations occurred in 36.75% of patients, with certain cancer types, including cutaneous melanoma, bladder cancer, and lung cancers, showing the highest mutation frequencies. DDR gene alterations were linked to significantly improved overall survival and progression-free survival in several cancers, particularly in patients receiving combined PD-1/CTLA-4 immunotherapy. A DDR signature of 34 genes was identified as a strong prognostic factor, showing enhanced immunotherapy responses. However, in cancer patients received ICIs, a threshold of two DDR mutations did not provide additional survival benefits compared to individual mutations. Immunotherapy-related DDR mutations were associated with elevated TMB and increased immune cell infiltration, suggesting enhanced anti-tumor immunity in tumor microenvironment.Conclusions The study highlights DDR gene alterations as reliable predictive biomarkers for ICI treatment responses, offering significant insights into personalized cancer therapies. It proposes the development of distinct DDR-based biomarkers for immunotherapy, emphasizing the clinical utility of these signatures in optimizing therapeutic strategies. The study underscores the need for prospective validation and further exploration of the underlying immunological mechanisms driving the observed clinical benefits. Additionally, it suggests that DDR mutation status could play a crucial role in enhancing immunotherapy outcomes across multiple malignancies.",
  "authors": [
    {
      "affiliations": [
        "Hepatic Surgery Center, Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China"
      ],
      "name": "Huang PengQun"
    },
    {
      "affiliations": [
        "Hepatic Surgery Center, Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China"
      ],
      "name": "Ze-yang Ding"
    }
  ],
  "title": "177 DNA damage repair family genomic alterations as a predictive biomarker for response to immune checkpoint inhibitors in multiple cancers",
  "uid": "eaa4e6ed-1a67-5a40-b10a-ad9b21cb5595"
}