Comprehensive analysis of DNA damage repair deficiency in 10,284 pan-cancer study
Yanni Xiao, Di Lu, Mingxing Lei, Wenzhuan Xie, Yaoxu Chen, Yating Zheng, Chunli Wang, Jing Zhao, Zhen Zhu, Xiaochen Zhao, Mengli Huang, Youen Lin, Zhongjun Li, Yang Li
Abstract
Background: Disruption of the DNA damage repair (DDR) gene is related to cancer progression, treatment selection, and is subjected to radiation and targeted therapies with limited success. This paper conducted a comprehensive analysis to explore the distribution of DDR mutations in Chinese pan-cancer patients. Methods: A total of 10,284 consecutive cases were analyzed in 24 cancer types [non-small cell lung cancer (NSCLC) 29.0%, liver 12.0%, colorectum 10.7%, etc.]. Tumor tissue samples were subjected to next generation sequencing (NGS) using a 381 gene panel incorporating 100 microsatellite loci. The association of deleterious somatic DDR mutation (del-sDDRmut) with tumor mutational burden (TMB), microsatellite instability (MSI), programmed cell death-ligand 1 (PD-L1) expression of pan-cancers was evaluated. Genomic and clinical data from public cohorts of immunotherapy were analyzed to demonstrate the association between del-sDDRmut and clinical survival. Results: Del-sDDRmut were found in 802 (7.6%) of all cases, and were most common in cancers of the endometrium, prostate, bladder, etc. cancer with a higher TMB also had a higher prevalence of mutations in DDR pathways. The results of the ridge regression analysis showed that 20 DDR genes were significantly associated with TMB [false discovery rate (FDR) <0.01]. A total of 8,899 patients had both TMB and MSI-data in pan-cancers. Seventy-four percent of patients with MSI-high (MSI-H) were accompanied by del-sDDRmut/TMB-high (TMB-H). The largest proportion of patients with microsatellite stability (MSS) with DDR mutations were classified as TMB-H. The top 6 tumors (NSCLC, melanoma, esophagus, head and neck, thyroid, and mediastinal) had the highest prevalence of PD-L1 ≥1%, and DDR mutations were significantly associated with a higher percent of PD-L1 positive (P<0.05). Furthermore, in the immune cohort analysis of NSCLC, patients with del-sDDRmut significantly improved median progression-free survival (mPFS) and median overall survival (mOS) compared to wild-type DDR patients (P=0.002 and P=0.043), with higher TMB observed (P<0.001). Conclusions: This study explored the association of DDR mutations with TMB, MSI-H, and PD-L1 expression, and revealed that patients with DDR mutations have a significantly improve prognosis than wild-type patients on immunotherapy.