129P Comprehensive analysis of DNA damage repair deficiency across 10,613 pan-cancer patients: Implications for drug development and therapy

Abstract

DNA damage repair (DDR) system play key roles in maintaining human genomic stability, disruption of which is observed in many cancers and related to cancer progression, therapeutic response and treatment selection. We aimed to conduct a comprehensive analysis to explore the DDR deficiency distribution in pan-cancer. A total of 10,613 consecutive cases across 24 cancer types from 6th January 2017 through 19th August 2019 were analyzed. A MasterView panel covered 381 genes and 100 MSI loci was performed to tissue sample obtained from tumor patients. The average depth of coverage for this assay is 1000×. Thirty-one DDR genes included in the NGS panel across seven main DDR pathways including BER, NER, MMR, FA, HR, NHEJ and DS. The association of DDR deficiency with TMB, MSI, PD-L1 of early stage cancers or advanced cancers with immune therapy were evaluated. DDR alteration were found in 802 (7.6%) of all cases and were most frequent in cancers of Endometrium (25.23%), Bladder/Urinary Tract (13.53), Intestine (12.40%), Colorectum (11.40%) and Cervix (10.50%). Cancer types with a higher TMB also had a higher mutation prevalence in DDR pathways. The results of ridge regression analysis showed that 20 DDR genes were significantly associated with TMB (FDR<0.01). Of DDR-altered cases, 79% (873/1104) were both MSS and TMB-Low (TMB <11.1 mut/MB). In terms of specific genes, patients with POLE, CHEK2, FANCC, MRE11A and MLH1 had the most proportion of TMB-H/MSS. The top five tumors with the highest prevalence of PD-L1 ≥ 1% were Mediastinal (91.67%), Head and neck (70.73%), Melanoma (60.71%), Esophagus (59.10%) and Thyroid(58.33%). DDR germline alteration were mainly present in cancers of Ovary (14.92%), Prostate (11.69%) and SCLC (10.67%), and have significantly higher TMB than those with DDR somatic mutations and wild type patients (P<0.001 for All). Our analysis of DDR pathways across the 10,613 samples of 24 tumor types in Chinese population explored the association of DDR alteration with TMB, MSI-H and PD-L1; and provided insight into the potential application of DDR deficiency in cancer risk, drug development and therapeutic response.