KMT2D Mutation Is Associated With Poor Prognosis in Non–Small-Cell Lung Cancer

Abstract Background Mixed-lineage leukemia protein 2 (MLL2 or KMT2D) is a histone methyltransferase whose mutation has been associated with a poor prognosis in cancer. We compared the characteristics and significance of KMT2D alterations in non–small-cell lung cancer (NSCLC) with those in small cell lung cancer (SCLC). Patients and Methods Tumors from 194 NSCLC patients with locally advanced or advanced disease and 64 SCLC patients underwent targeted-exome sequencing. The association of KMT2D mutation with overall survival (OS) and progression-free survival (PFS) was measured using Kaplan-Meier methods and further evaluated using multivariable Cox proportional hazards regression model adjusting for known clinical prognostic features. Results The KMT2D mutation rate was 17.5% (34 of 194) in NSCLC. Patients with mutant KMT2D had significantly lower median OS (9.97 vs. 30.2 months; P P  = .0004) compared with patients with wild-type KMT2D. The KMT2D mutation was significantly more common in females ( P  = .017). Using a multivariate Cox regression model, KMT2D mutation was one of the most significant prognostic factors in NSCLC: hazard ratio (HR) for OS, 2.79 (95% confidence interval [CI], 1.8-4.33; P P  = .001). In contrast, the KMT2D mutation rate in SCLC was 32.8% (21 of 64) and showed no sex bias ( P  = .874). No significant change was found in survival in association with the KMT2D mutation in SCLC (OS, P  = .952; PFS, P = .744). Conclusion The KMT2D mutation was associated with reduced survival in NSCLC but not in SCLC.