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The present retrospective study evaluated the association of mutations in KMT2D, an epigenetic regulator, with survival in non–small-cell lung cancer (NSCLC) and compared it with small-cell lung cancer (SCLC). Tumors from 194 patients with locally advanced or advanced NSCLC and 64 patients with SCLC underwent targeted-exome sequencing. The KMT2D mutation rate was 17.5% in NSCLC and 32.8% in SCLC. KMT2D mutation is associated with reduced survival in NSCLC but not SCLC.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).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.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 < .0001) and median PFS (8.46 vs. 24.1 months; 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 < .0001) and HR for PFS, 1.99 (95% CI, 1.32-3.01; 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).The KMT2D mutation was associated with reduced survival in NSCLC but not in SCLC.