Association of high tumor mutation (TMB) with DNA damage repair (DDR) alterations and better prognosis in ovarian cancer.

Abstract

5512 Background: Defects in DNA damage repair (DDR) system may lead to genomic instability and manifest as increased tumor mutation burden (TMB) in multiple types of cancers. But the prognostic value of TMB and association between DDR and TMB in ovarian cancer is still unclear. Methods: Whole-exome sequencing data of 434 ovarian tumors from The Cancer Genome Altas (TCGA) and next generation sequencing (NGS) data of 93 ovarian tumors from 3D Medicines were analyzed to explore the association between 21 cancer-related DDR genes and TMB, defined as number of somatic non-synonymous mutations. We also performed analysis of clinical data from TCGA to identify the impact of TMB on ovarian cancer prognosis. Results: 27.4% of ovarian tumors in TCGA and 40.9% in 3D Med harbored at least one DDR alteration. The most frequently mutated genes were POLE (21%), BRCA1 (5.1%), BRCA2 (4.1%), ATM (3.0%), FANCA (2.5%), PALB2 (2.3%), FANCD2 (2.1%), and ATR (2.1%) in TCGA, and BRCA1 (12.9%), BRCA2 (10.8%), ATM (5.4%), RAD51 (3.2%), BRIP1 (3.2%), FANCD2 (3.2%), and PALB2 (3.2%) in 3D Med. Any DDR alteration was significantly associated with higher TMB in both TCGA (P < 0.00) and 3D Med (P = 0.021). Any two DDR gene alterations were associated with even much higher degree of TMB in both TCGA (P < 0.00) and 3D Med (P = 0.03) compared with DDR wild type. Co-mutated TP53 and any DDR significantly associated with higher TMB in both TCGA (P < 0.00) and 3D Med (P = 0.02). Prognosis analysis was performed on patients from TCGA. High TMB (cut off as median) was associated with significantly longer DFS (16.4m vs. 14.1m, HR 0.83, P = 0.04) and OS (41.0m vs. 32.1m, HR 0.77, P < 0.00). Moreover, median PFS for patients with and without DDR alterations was 19.2m and 16.7m (P = 0.07). Median OS was 54.6m and 41.5m respectively (P = 0.02). Conclusions: DDR deficiency is prevalent in ovarian cancer and associated with higher TMB. High TMB was associated with more favorable DFS and OS in ovarian cancer patients. Our results suggest that DDR gene alterations may correlated with anti-tumor immunity in forms of increased TMB, which is known to increase the neoantigen load of tumors. This may assist with the selection of ovarian cancer patients likely to benefit from immunotherapy.