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.

Pancancer analysis of the prognostic and immunological role of FANCD2: a potential target for carcinogenesis and survival

“…GO and KEGG enrichment analysis revealed that FANCD2 -related genes are involved in numerous potential pathways, particularly in cell cycle and DDR pathways. The DDR process plays a significant role in cancer susceptibility, progression, and response to treatment [ 45 ]. The FA pathway, which is activated in response to DNA damage, can maintain genomic stability during the DDR to prevent cancer [ 46 ].…”

Analysis of the nischarin expression across human tumor types reveals its context-dependent role and a potential as a target for drug repurposing in oncology

“…In line with the NISCH so far described biological roles [ 7 – 12 ], and regardless of the tumor type, decreased NISCH expression was associated with activation of metabolic pathways that allow increased tumor growth. In addition, in “NISCH low” phenotype, regardless of the prognostic role, pathways that characterize survival in hypoxic and nutrient deprived conditions like reactive oxygen species pathway, unfolded protein response [ 82 ], and DNA repair [ 83 ], were enriched. This is in line with our finding that nischarin levels are lower in most cancers compared to healthy tissues, since these are critical events for tumor progression.…”

Extrachromosomal DNA Couples with ATM-mediated DNA Damage Response for Genome Instability in Tumors

“…The HRD scores of 258 ecDNA+ and 2383 ecDNA-samples among 12 tumor types were compared (except for LGG and OV, because there are no LGG and OV samples mapped to our data). DDR score is a method to quantify the tumor signature of DNA damage repair pathways and was calculated based on the previous study 42 . We used 20 genes they provided (POLQ, EXO1, EME1, BRIP1, FANCA, BLM, FANCI, BRCA2, XRCC2, RAD51, DLX5, UBE2T, BRCA1, FANCB, FANCD2, FEN1, XRCC3, BARD1, GEN1 and PRKDC) as a tumor-related core DDR gene set 42 .…”

“…DDR score is a method to quantify the tumor signature of DNA damage repair pathways and was calculated based on the previous study 42 . We used 20 genes they provided (POLQ, EXO1, EME1, BRIP1, FANCA, BLM, FANCI, BRCA2, XRCC2, RAD51, DLX5, UBE2T, BRCA1, FANCB, FANCD2, FEN1, XRCC3, BARD1, GEN1 and PRKDC) as a tumor-related core DDR gene set 42 . Gene Set Variation Analysis (GSVA) analysis was implemented in R package GSVA (v1.38.2) 43 to calculate DDR scores based on this core DDR gene set for each TCGA sample.…”