Abstract
KRAS is a key oncogenic driver in lung adenocarcinoma (LUAD). Chromatin-remodeling gene SMARCA4 is comutated with KRAS in LUAD; however, the impact of SMARCA4 mutations on clinical outcome has not been adequately established. This study sought to shed light on the clinical significance of SMARCA4 mutations in LUAD. The association of SMARCA4 mutations with survival outcomes was interrogated in four independent cohorts totaling 564 patients: KRAS-mutant patients with LUAD who received nonimmunotherapy treatment from (a) The Cancer Genome Atlas (TCGA) and (b) the MSK-IMPACT Clinical Sequencing (MSK-CT) cohorts; and KRAS-mutant patients with LUAD who received immune checkpoint inhibitor-based immunotherapy treatment from (c) the MSK-IMPACT (MSK-IO) and (d) the Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) immunotherapy cohorts. Of the patients receiving nonimmunotherapy treatment, in the TCGA cohort (n=155), KRAS-mutant patients harboring SMARCA4 mutations (KS) showed poorer clinical outcome [P=6e-04 for disease-free survival (DFS) and 0.031 for overall survival (OS), respectively], compared to KRAS-TP53 comutant (KP) and KRAS-only mutant (K) patients; in the MSK-CT cohort (n=314), KS patients also exhibited shorter OS than KP (P=0.03) or K (P=0.022) patients. Of patients receiving immunotherapy, KS patients consistently exhibited the shortest progression-free survival (PFS; P=0.0091) in the MSK-IO (n=77), and the shortest PFS (P=0.0026) and OS (P=0.0014) in the WFBCCC (n=18) cohorts, respectively. Therefore, mutations of SMARCA4 represent a genetic factor leading to adverse clinical outcome in lung adenocarcinoma treated by either nonimmunotherapy or immunotherapy.
Highlights
KRAS is a key oncogenic driver in lung adenocarcinoma (LUAD).Chromatin-remodeling gene SMARCA4 was co-mutated with KRAS in LUAD; the impact of SMARCA4 mutations on clinical outcome has not been adequately established
Conclusions mutations of SMARCA4 represent a genetic factor that lead to adverse clinical outcome in lung adenocarcinoma treated by either non-immunotherapy or immunotherapy
Great strides have been made in recent years with the development of immune checkpoint inhibitor treatment targeting PD-1/PD-L1 mediated immunosuppression, which have shown efficacy in up to 30% of Non-small cell lung cancer (NSCLC)
Summary
The association of SMARCA4 mutations with survival outcomes was interrogated in 4 independent cohorts totaling 564 patients: KRAS-mutant patients withLUAD who received non-immunotherapy treatment from 1) The Cancer Genome Atlas (TCGA) and 2) the MSK-IMPACT Clinical Sequencing (MSK-CT) cohorts; and KRAS-mutant patients with LUAD who received immune checkpoint inhibitor-based immunotherapy treatment from 3) the MSK-IMPACT (MSK-IO) and 4) the Wake ForestBaptist Comprehensive Cancer Center (WFBCCC) immunotherapy cohorts. LUAD who received non-immunotherapy treatment from 1) The Cancer Genome Atlas (TCGA) and 2) the MSK-IMPACT Clinical Sequencing (MSK-CT) cohorts; and KRAS-. Mutant patients with LUAD who received immune checkpoint inhibitor-based immunotherapy treatment from 3) the MSK-IMPACT (MSK-IO) and 4) the Wake Forest. Baptist Comprehensive Cancer Center (WFBCCC) immunotherapy cohorts. For the Cancer Genome Atlas (TCGA) cohort, matched somatic mutation, gene expression and clinical data of 560 patients with LUAD were retrieved. Sequencing Cohort and extracted the data of LUAD patients [27]. We extracted the 127 LUAD patients who were treated with immunotherapy between. March 1, 2015 and November 30, 2017 at the Wake Forest Baptist Comprehensive. Genomic profiles were available for 39 patients who were enrolled into the Wake Forest Precision
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