A score of DNA damage repair pathway with the predictive ability for chemotherapy and immunotherapy is strongly associated with immune signaling pathway in pan-cancer.

Abstract

DNA damage repair (DDR) is critical in maintaining normal cellular function and genome integrity and is associated with cancer risk, progression, and therapeutic response. However, there is still a lack of a thorough understanding of the effects of DDR genes’ expression level in cancer progression and therapeutic resistance. Therefore, we defined a tumor-related DDR score (TR-DDR score), utilizing the expression levels of 20 genes, to quantify the tumor signature of DNA damage repair pathways in tumors and explore the possible function and mechanism for the score among different cancers. The TR-DDR score has remarkably predictive power for tumor tissues. It is a more accurate indicator for the response of chemotherapy or immunotherapy combined with the tumor-infiltrating lymphocyte (TIL) and G2M checkpoint score than the pre-existing predictors (CD8 or PD-L1). This study points out that the TR-DDR score generally has positive correlations with patients of advanced-stage, genome-instability, and cell proliferation signature, while negative correlations with inflammatory response, apoptosis, and p53 pathway signature. In the context of tumor immune response, the TR-DDR score strongly positively correlates with the number of T cells (CD4+ activated memory cells, CD8+ cells, T regs, Tfh) and macrophages M1 polarization. In addition, by difference analysis and correlation analysis, COL2A1, MAGEA4, FCRL4, and ZIC1 are screened out as the potential modulating factors for the TR-DDR score. In summary, we light on a new biomarker for DNA damage repair pathways and explore its possible mechanism to guide therapeutic strategies and drug response prediction.