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

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 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.

Figure 1.

Spectrum of SMARCA4 alterations by class and association with SMARCA4 protein expression. (A) The distribution of Class 1 SMARCA4 alterations (n=212) and protein expression (n =62). (B) The distribution of Class 2 SMARCA4 alterations (n=95) and protein expression (n =24). Green QLQ, Gln, Leu, Gln motif; Red HSA, helicase/SANT-associated domain; Blue BRK, Brahma and Kismet domain; Yellow DEXDc, DEAD-like helicase superfamily domain; Purple SNF2_N, SNF2 family N-terminal domain; Orange HELICc, helicase superfamily C-terminal domain; Pink Bromo, bromodomain.

Figure 2.

Genomic context of SMARCA4 alterations. (A) Most frequent co-occurring alterations by SMARCA4 alteration. (B) Distribution of SMARCA4 alteration by commonly altered gene subgroups in NSCLC. (C) Frequency of altered individual genes within SMARCA4 mutant vs SMARCA4 wildtype subgroups. Genes labeled red were associated with significantly differential PD-L1 expression (q value <0.10). (D) Distribution of SMARCA4, STK11, KRAS, and KEAP1 alterations within NSCLC cohort.

Figure 3.

Survival by SMARCA4 alteration class. (A) Overall survival among all patients, with multivariate model (right). (B) Overall survival among patients with KRAS mutations, with multivariate model (right).

Figure 4.

PD-L1 expression, tumor mutational burden, and immune checkpoint inhibitor (ICI) outcomes. (A) Overall survival among patients with SMARCA4 alterations who did and did not receive ICIs. (B) Tumor mutational burden (TMB) by SMARCA4 alteration class. (C) PD-L1 expression frequency by SMARCA4 alteration class. (D) Overall response rate by SMARCA4 alteration class. (E) Progression-free survival by SMARCA4 alteration class. (F) Overall survival by SMARCA4 alteration class.