Non-small cell lung cancer with loss of expression of the SWI/SNF complex is associated with aggressive clinicopathological features, PD-L1-positive status, and high tumor mutation burden. (December 2019) - Naito, Tomoyuki
Highlights: SWI/SNF is a chromatin remodeling complex that regulates gene expression. We evaluated expression of SWI/SNF subunits in NSCLC using immunohistochemistry. Loss of expression of the SWI/SNF complex was observed in 5.5% of 1013 NSCLC cases. NSCLC with loss of SWI/SNF showed aggressive clinicopathological features. PD-L1-positivity and tumor mutation burden are higher in NSCLC with loss of SWI/SNF. Abstract: Objectives: Loss of the chromatin remodeling SWItch/Sucrose Non-fermentable (SWI/SNF) complex is implicated in the pathogenesis of several types of neoplasms. The aim of this study was to examine the clinicopathological features of non-small cell lung cancer (NSCLC) with loss of expression of the SWI/SNF complex. Materials and methods: Specimens from a total 1013 NSCLC cases used for tissue microarrays (TMAs) were immunohistochemically examined for expression of SWI/SNF complex (BAF) subunits, namely SMARCA4, SMARCA2, ARID1A, and ARID1B. We examined the clinicopathological features and PD-L1 expression status in NSCLC cases with loss of expression of one or more subunits of the SWI/SNF complex (BAF-Loss). Moreover, we compared the tumor mutation burden (TMB) between NSCLC cases with BAF-Loss and those with intact expression of the four subunits (BAF-Intact). Results: Using TMA, BAF-Loss was observed in 5.4% of cases (SMARCA4: 2.4%, SMARCA2: 2.4%, ARID1A: 1.3%, and ARID1B: 0.3%). Concurrent loss of expression of two or more subunits of the SWI/SNF complex was detected in 0.7% of cases. BAF-Loss was significantly associated with smoking history, young age, male sex, pulmonary emphysema/bullae, large invasive tumor size, pleural invasion, vascular invasion, solid-predominant morphology, and absence of a lepidic growth component. A higher proportion of PD-L1-positive cases was observed among NSCLC patients with BAF-Loss than BAF-Intact (42% vs 26%, P < 0.01). In stage I NSCLC, SWI/SNF-Loss (n = 23) was associated with shorter overall survival (HR: 2.43; 95% CI: 1.18–5.01; P = 0.01) and recurrence-free survival (HR: 2.22; 95% CI: 1.17–4.24; P < 0.01) compared to BAF-Intact (n = 563). The degree of TMB was significantly higher among NSCLC patients with BAF-Loss (n = 3) than BAF-Intact (n = 7) (median 437 vs 113 mutations/whole-exome, P = 0.02). Conclusion: The current results suggest that loss of SWI/SNF expression in NSCLC is associated with aggressive clinicopathological features, PD-L1-positive status and high TMB.