Objective: Immune checkpoint inhibitors (ICIs) have achieved remarkable results in cancer treatments. However, there is no effective predictive biomarker for gastrointestinal (GI) cancer. Methods: We conducted integrative analyses of the genomic and survival data of ICI-treated GI cancer patients from the Memorial Sloan Kettering Cancer Center cohort (MSK-GI, n = 227), the Janjigian cohort (n = 40), and the Peking University Cancer Hospital & Institute cohort (PUCH, n = 80) to determine the possible associations between DNA damage response and repair (DDR) gene mutations and clinical outcomes. Data from The Cancer Genome Atlas database were analyzed to determine the possible correlations between DDR gene mutations and the tumor microenvironment. Results: In the MSK cohort, the presence of ≥ 2 DDR gene mutations was correlated with prolonged overall survival (OS). The Janjigian and PUCH cohorts further confirmed that subgroups with ≥ 2 DDR gene mutations displayed a prolonged OS and a higher durable clinical benefit. Furthermore, the DDR gene mutation load could be considered as an independent prognostic factor, and exhibited a potential predictive value for survival in GI cancer patients treated with ICIs. Mechanistically, we showed that the presence of ≥ 2 DDR gene mutations was correlated with higher levels of tumor mutation burden, neoantigen, and T cell infiltration. Conclusions: The DDR gene mutation status was correlated with favorable clinical outcomes in GI cancer patients receiving ICIs, which could serve as a potential biomarker to guide patient selection for immunotherapy.

Yujiao Wang;Xi Jiao;Shuang Li;Huan Chen;Xin Wei;Chang Liu;Jifang Gong;Xiaotian Zhang;Xicheng Wang;Zhi Peng;Changsong Qi;Zhenghang Wang;Yanni Wang;Na Zhuo;Jianling Zou;Henghui Zhang;Jian Li;Lin Shen;Zhihao Lu

Department of Gastrointestinal Oncology,Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education),Peking University Cancer Hospital&Institute,Beijing 100142,China;Department of Gastric&Colorectal Surgery,The First Hospital of Jilin University,Changchun 130021,China;Genecast Precision Medicine Technology Institute,Beijing 100192,China;Life Sciences Institute,Zhejiang University,Hangzhou 310058,China;Institute of Infectious Diseases,Beijing Ditan Hospital,Capital Medical University,Beijing 100015,China

癌症生物学与医学（英文版）

[1]Yujiao Wang;Xi Jiao;Shuang Li;Huan Chen;Xin Wei;Chang Liu;Jifang Gong;Xiaotian Zhang;Xicheng Wang;Zhi Peng;Changsong Qi;Zhenghang Wang;Yanni Wang;Na Zhuo;Jianling Zou;Henghui Zhang;Jian Li;Lin Shen;Zhihao Lu-.Alterations in DNA damage response and repair genes as potential biomarkers for immune checkpoint blockade in gastrointestinal cancer)[J].癌症生物学与医学（英文版）,2022(08):1139-1149

Janjigian,PUCH

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