1132P DNA damage repair mutation burden (DDRMB) was significantly associated with TMB and predicted prognosis of immunotherapy in melanoma

Abstract

Tumor mutation burden (TMB) was emerging biomarker and was associated with prognosis of immunotherapy. Mutations in DNA damage repair (DDR) pathway hampers DNA damage repair and would lead to accumulation of mutations, which might increase TMB. Although there were sporadic reports about association between mutation in certain DDR genes (such as TP53, BRCA1/2, BER) and tumor prognosis, the association between DNA damage repair mutation burden (DDRMB), and TMB and prognosis of immunotherapy was not well evaluated yet. We retrospectively analyzed the whole exome sequencing (WES) results of 110 and 64 patients from 2 published prospective studies in melanoma and their prognosis of immunotherapy. 201 genes were defined as DDR genes. Correlation between DDRMB and TMB was analyzed. Difference in prognosis was conveyed by Kaplan-Meier analysis. Difference of TMB between groups were conveyed by T test. Strong correlation between DDRMB and TMB was revealed (R2=0.8798). TMB in patients with DDR mutations was significantly higher than others (P<0.001). Patients were divided into 4 subgroups with ≥ 3, 2, 1 and 0 DDR mutations. Pairwise comparison among each group indicated that groups with more DDR mutations contained significantly higher TMB than groups with less mutations (P<0.001). The overall survival (OS) in patients with DDR mutation was significantly higher than patients without DDR mutation (P=0.05). Besides, subgroups with ≥ 3 DDR mutations showed numerically longer OS than patient with less mutations. DDR mutation burden was highly correlated with TMB. Melanoma patients with higher DDRMB bears higher TMB, and showed worse OS in immunotherapy. DDRMB might be a potential biomarker for immunotherapy in melanoma. Larger trials are needed for further validation.