Role of synthetic lethal mutations for the immune response: Exploratory studies of two non-small cell lung cancer cohorts and two pan-cancer cohorts.

Abstract

e21137 Background: Synthetic lethality (SL) is a phenomenon in which mutations in either of two genes do not affect cell survival, but abnormalities in both genes lead to cell death. However, it is little known whether synthetic lethality affects the response of immunotherapy. Methods: Synthetic lethal gene pairs come from the SynLethDB database, which provides a webserver to calculate the confidence scores for each SL pair by integrating individual scores derived from different evidence sources. The analysis included two immunotherapy cohorts of non-small cell lung cancer (Chan, 2015 and Hellmann, 2018) and two solid tumor cohorts (Morris, 2019 and Berger, 2020) in the published literature. Synthetic lethal gene pairs were defined as genes with a score > 0.5. The patients with synthetic lethal gene pairs were divided into one subgroup (SL group), and the other patients were divided into another subgroup (non-SL group). Kaplan-Meier analysis was used to determine progression-free (PFS) and overall survival (OS). Results: Overall, four public cohorts with 12271 patients were included in the analysis. In the cohort of Chan 2015, a total of 34 patients with non-small cell lung cancer (NSCLC) received immunotherapy. Among them, 21 patients were in the SL group and 13 were in the non-SL group, with the former having a significantly longer PFS (p = 0.0345). In the other cohort of immunotherapy (Hellmann, 2018), 90 (37.5%) patients with NSCLC were in SL group. PFS for patients with SL group was significantly longer than those in non-SL group (p = 0.0261). In cohorts with pan-cancer, patients in Morris 2019 cohort (n = 1661) received immunotherapy and patients in Berger 2020 cohort (n = 10336) received other kinds of treatment. A better prognosis was observed in patients with the immunotherapy in SL group than non-SL group (p < 0.0001). In contrast, patients with other kinds of treatment had a significantly worse prognosis in SL group than non-SL group (p < 0.0001). Conclusions: Our results suggested that synthetic lethal gene pairs containing scores greater than 0.5 may be associated with higher progression-free survival in patients with various types of tumors. The specific reasons for the impact still need to be further explored.