Characterizing the Clinical and Molecular Profile of SETD2-Mutated Lung Adenocarcinoma

Introduction: SETD2 is an understudied gene that encodes for a histone methyltransferase implicated in lung cancer tumorigenesis and is found in up to 10% of all non-small cell lung cancer. With the largest cohort to date, we aim to elucidate the clinicopathologic characteristics and prognosis of SETD2-mutated lung adenocarcinoma. Methods: We obtained molecular genetics reports of lung cancer seen between 1 January 2015 and 4 January 2024. We identified all SETD2-mutated cancer and identified 500 consecutive cases prior to 4 January 2020 as a control group. Non-recurrent adenocarcinomas were included. Patient and tumor characteristics and recurrence-free survival (RFS) were compared. Fisher's exact, Wilcoxon rank sum, and log-rank tests were used when appropriate. Kaplan-Meier plots and Cox proportional hazards models were used to analyze recurrence-free survival. Results: A total of 67 SETD2-mutated lung and 174 non-SETD2-mutated lung adenocarcinomas met inclusion criteria. SETD2-mutated tumors presented at earlier stages (55.2% vs. 17.8% stage I, 11.9% vs. 48.3% stage IV, p < 0.001). SETD2-mutated adenocarcinoma had a higher number of genetic mutations (median: 11 IQR: [8-15] vs. 7 [5-10], p < 0.001). In a univariable Cox analysis, SETD2 mutation was associated with improved RFS (HR 0.53 95% CI: [0.33-0.85], p = 0.008). In a covariate-adjusted model, SETD2 mutation trended towards improved RFS (0.71 [0.43-1.18], p = 0.10). Conclusions: These data suggest SETD2-mutated lung adenocarcinoma presents at significantly earlier stages, has a unique molecular profile compared to non-mutated tumors, and trends towards improved RFS in early-stage tumors. Future study is warranted on both patient outcomes and immunopathologic characteristics of SETD2-mutated lung adenocarcinoma.