The Genomic Landscape of SMARCA4 Alterations and Associations with Outcomes in Patients with Lung Cancer

作者：Adam J. Schoenfeld, Chai Bandlamudi, Jessica A. Lavery, Joseph Montecalvo, Azadeh Namakydoust, Hira Rizvi, Jacklynn V. Egger, Carla P. Concepcion, Sonal Paul, Maria E. Arcila, Yahya Daneshbod, Jason C. Chang, Jennifer L. Sauter, Amanda Beras, Marc Ladanyi, Tyler Jacks, Charles M. Rudin, Barry S. Taylor, Mark T.A. Donoghue, Glenn Heller, Matthew D. Hellmann, Natasha Rekhtman, Gregory J. Riely · 发表于：Clinical Cancer Research · 年份：2020 · DOI：10.1158/1078-0432.ccr-20-1825 · 被引用次数：293 · 研究领域：Chromatin Remodeling and Cancer、Cancer Mechanisms and Therapy、Mechanisms of cancer metastasis

Abstract Purpose: SMARCA4 mutations are among the most common recurrent alterations in non–small cell lung cancer (NSCLC), but the relationship to other genomic abnormalities and clinical impact has not been established. Experimental Design: To characterize SMARCA4 alterations in NSCLC, we analyzed the genomic, protein expression, and clinical outcome data of patients with SMARCA4 alterations treated at Memorial Sloan Kettering. Results: In 4,813 tumors from patients with NSCLC, we identified 8% (n = 407) of patients with SMARCA4-mutant lung cancer. We describe two categories of SMARCA4 mutations: class 1 mutations (truncating mutations, fusions, and homozygous deletion) and class 2 mutations (missense mutations). Protein expression loss was associated with class 1 mutation (81% vs. 0%, P < 0.001). Both classes of mutation co-occurred more frequently with KRAS, STK11, and KEAP1 mutations compared with SMARCA4 wild-type tumors (P < 0.001). In patients with metastatic NSCLC, SMARCA4 alterations were associated with shorter overall survival, with class 1 alterations associated with shortest survival times (P < 0.001). Conversely, we found that treatment with immune checkpoint inhibitors (ICI) was associated with improved outcomes in patients with SMARCA4-mutant tumors (P = 0.01), with class 1 mutations having the best response to ICIs (P = 0.027). Conclusions: SMARCA4 alterations can be divided into two clinically relevant genomic classes associated with dif...