The Genomic Landscape of SMARCA4 Alterations and Associations with Outcomes in Patients with Lung Cancer
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- 24 July 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 26 (21), 5701-5708
- https://doi.org/10.1158/1078-0432.ccr-20-1825
Abstract
Purpose: SMARCA4 mutations are among the most common recurrent alterations in 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 4813 tumors from patients with NSCLC, we identified 8% (n= 407) 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-occured more frequently with KRAS, STK11, and KEAP1 mutations compared to SMARCA4 wildtype 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 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 differential protein expression as well as distinct prognostic and treatment implications. Both classes co-occur with KEAP1, STK11, and KRAS mutations, but individually represent independent predictors of poor prognosis. Despite association with poor outcomes, SMARCA4-mutant lung cancers may be more sensitive to immunotherapy.Keywords
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Funding Information
- Memorial Sloan Kettering Cancer Center (P30 CA008748)
- MSK, ACS Postdoctoral Fellowship (130361-PF-17-009-01-CDD)
- Damon Runyon Cancer Research Foundation (CI-98-18)
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