Association of MLL2 mutation positive non-small cell lung cancer with prognosis.

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11598 Background: Myeloid/lymphoid or mixed-lineage leukemia protein 2 (MLL2) is an epigenetic regulator expressed in many tissues. Although MLL2 mutations are associated with poor prognosis in different types of cancer, the clinical impact of this gene in lung cancer remains unclear. Here, we evaluated the clinical and genomic characteristics of MLL2 alteration in non-small cell lung cancer (NSCLC) and compared it to small cell lung cancer (SCLC) Methods: Between 2014 and 2016 tumor samples of 194 Stage III and IV NSCLC patients and 50 SCLC patients underwent targeted-exome sequencing. The association of MLL2 mutation with survival outcomes was measured using Kaplan–Meier methods (PFS, OS). Cox’s proportional hazards regression model was performed for multivariate survival analyses with known clinical prognostic features. All tests were two-sided and p-values = 0.05 were considered statistically significant. Results: The MLL2 mutation rate was 17.5% (N=34) in NSCLC. Patients with mutant MLL2 had significantly lower overall survival (OS) (9.97 vs. 30.2 months, p < 0.0001) and progression-free survival (PFS) (8.46 vs. 24.1 month, p = 0.0007) compared to those with wild type MLL2. The median overall survival in the entire NSCLC cohort was 23.3 months (95% CI: 16.5 – 34.4). Interestingly, MLL2 mutation was significantly more common in females (p = 0.017). There was no significant association of MLL2 mutation status with age, smoking history, race or histology . Using a multivariate Cox regression model with adjustments based on tumor stage, smoking histology and chemotherapy, MLL2 mutation remained the most remarkable prognostic factor in NSCLC: OS Hazard Ratio 2.79, p = 0.0001 and PFS Hazard Ratio 1.99, p < 0.001. By comparison, the MLL2 mutation rate in SCLC was 24% (N=12) and showed no gender bias (p=0.874). There was no significant decrease in survival associated with MLL2 mutation in SCLC (OS p = 0.966, PFS p = 0.641). Conclusions: This study demonstrates that MLL2 mutation specifically impacts survival outcome only in NSCLC but not SCLC.