Clinicopathologic Characteristics of BRG1-Deficient NSCLC
| Autor: | Ibiayi Dagogo-Jack, Alice T. Shaw, Alexa B. Schrock, Siraj M. Ali, Nicholas A. Jessop, Marina Kem, Mari Mino-Kenudson, J. Lee, Jeffrey S. Ross, Jochen K. Lennerz |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Oncology medicine.medical_specialty Chemotherapy business.industry medicine.medical_treatment EZH2 STK11 Immunotherapy medicine.disease_cause medicine.disease 03 medical and health sciences 030104 developmental biology 0302 clinical medicine 030220 oncology & carcinogenesis Internal medicine SMARCA4 Medicine Immunohistochemistry KRAS business Lung cancer |
| Zdroj: | Journal of Thoracic Oncology. 15:766-776 |
| ISSN: | 1556-0864 |
| Popis: | Introduction Ten percent of NSCLCs harbor mutations in SMARCA4, the gene encoding the SWItch/Sucrose Non-Fermentable ATPase BRG1. In preclinical models, BRG1 inactivation increases tumor aggressiveness but enhances sensitivity to drugs that target oxidative phosphorylation and inhibit SMARCA2, EZH2, CDK4, or CDK6. To facilitate translation of preclinical findings into clinical studies exploiting these therapeutic vulnerabilities, we assessed the clinical features of patients with tumors harboring BRG1-inactivating mutations. Methods Data sets from Massachusetts General Hospital and Foundation Medicine were reviewed to determine the prevalence of SMARCA4-mutant NSCLC and describe its clinicopathologic characteristics. BRG1 expression was evaluated by immunohistochemistry and correlated with SMARCA4 mutations. Treatment outcomes were retrospectively assessed. Results We detected SMARCA4 genomic alterations in 9% (n = 117 of 1422) and 11% (n = 3188 of 27,281) of NSCLCs in the institutional and Foundation Medicine data sets, respectively. In both cohorts, truncating mutations comprised over one-third of SMARCA4 alterations. Twenty-nine of 64 SMARCA4-mutant NSCLCs (45%) assessed for BRG1 expression reported loss of expression, most (90%) of which had truncating SMARCA4 mutations. Overall, 84% (n = 26 of 31) of evaluated NSCLCs with truncating SMARCA4 mutations lacked BRG1 expression. Deficient BRG1 expression was predominantly detected in adenocarcinomas with co-occurring mutations in KRAS, TP53, KEAP1, and STK11. Among patients with BRG1-deficient NSCLC who received first-line platinum doublet chemotherapy (n = 11) or chemotherapy plus immunotherapy (n = 5), median progression-free survival was 38 days and 35 days, respectively. Conclusions BRG1 deficiency is enriched in NSCLCs with truncating SMARCA4 mutations. Clinical outcomes are poor in this molecular subgroup, highlighting the importance of developing novel strategies to target unique vulnerabilities associated with the BRG1-deficient state. |
| Databáze: | OpenAIRE |
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