Background: SMARCA4-deficient lung cancer is an undifferentiated lung cancer subtype associated with poor prognosis and morphological features that make them challenging to distinguish from sarcoma. These tumors are known to be resistant to standard of care surgery, radiation, and chemotherapy. Recent case reports suggest that these tumors might be resistant to immunotherapy. An assessment of the genomic and transcriptomic features of SMARCA4- deficient thoracic tumors may identify potential novel targets and treatment strategies for this new WHO lung cancer classification.

Methods: We retrospectively analyzed de-identified NGS data from 8,484 thoracic formalin-fixed, paraffin- embedded tumor biopsies from lung cancer patients sequenced using the Tempus|xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage; whole-exome capture RNA-seq). Tumor-normal match sequencing was performed for all tumors, enabling the detection of incidental germline alterations across 46 genes. SMARCA4-deficiency was defined as tumors with a pathogenic or likely pathogenic SMARCA4 single nucleotide variant, insertion/deletion, or copy number alteration. Statistical significance was determined using Fisher’s exact test and Wilcoxon rank-sum tests.

Results: SMARCA4-deficiency was detected in 370 (4.4%) tumors, of which over 80% were stage III or IV. SMARCA4 deficient tumors included more male patients (63% vs 49%, p<0.001) and younger age at diagnosis (median 64 vs 68 years, p <0.001). There were more patients with high tumor mutational burden (TMB-H, !10 mutations per megabase) (34% vs 15%, p<0.001), and fewer patients with positive PD-L1 immunohistochemical staining (44% vs 54%, p=0.009) compared to SMARCA4 wild-type tumors. Microsatellite instability status occurred at similar low frequencies across SMARCA4-deficient vs wild-type tumors (0.8% vs 0.5%, p=0.5). SMARCA4- deficient tumors showed enrichment for somatic mutations in TP53 (71% vs 47%, q<0.001), STK11 (22% vs 6.8%, q<0.001), KEAP1 (15% vs 4.2%, q<0.001), and CDKN2A (15% vs 5.9%, q<0.001) compared to wild-type. Tumor normal-match sequencing identified incidental germline mutations in MUTYH (2.2%), ATM (1.1%), ATP7B (0.5%), and MSH6 (0.5%) for SMARCA4- deficient tumors. RNA-sequencing analysis confirmed reduced transcriptional expression of SMARCA4 (p<0.001), CD274 (PD-L1; p<0.001), TNFRSF18 (p<0.001), and TNFRSF4 (p=0.035) in deficient tumors vs wild-type. Furthermore, SMARCA4-deficient tumors revealed reduced infiltration of CD4+ T cells (19% vs 22%, p<0.001).

Conclusions: This study reveals the unique genomic and transcriptional characteristics of SMARCA4-deficient lung tumors. Further studies are needed to assess the impact of immunotherapies and targeted therapies among this patient population.

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