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; Li Yang

doi:10.21037/atm-21-5449

Comprehensive analysis of DNA damage repair deficiency in 10,284 pan-cancer study

Ann Transl Med. 2021 Nov;9(22):1661. doi: 10.21037/atm-21-5449.

Authors

Yanni Xiao^#^{1

2}, Di Lu^#³, Mingxing Lei¹, Wenzhuan Xie⁴, Yaoxu Chen⁴, Yating Zheng⁴, Chunli Wang¹, Jing Zhao⁴, Zhen Zhu⁵, Xiaochen Zhao⁴, Mengli Huang⁴, Youen Lin⁶, Zhongjun Li², Li Yang¹

Affiliations

¹ 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, China.
² Department of Blood Transfusion, Laboratory of Radiation Biology, The Second Affiliated Hospital, Third Military Medical University, Chongqing, China.
³ Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
⁴ The Medical Department, 3D Medicines Inc., Shanghai, China.
⁵ Department of Thoracic Surgery, Kunshan Hospital of Traditional Chinese Medicine, Kunshan, China.
⁶ Department of Oncology, Jieyang Yuedong Cancer Hospital, Jieyang, China.

^# Contributed equally.

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-sDDR^mut) 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-sDDR^mut and clinical survival.

Results: Del-sDDR^mut 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-sDDR^mut/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-sDDR^mut 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.

Keywords: DNA damage repair deficiency (DDR deficiency); pan-cancer; somatic mutation; tumor mutational burden (TMB).