A pan-cancer analysis of SMARCA4 alterations and the unique clinicogenomic characteristics associated with SMARCA4 mutation types.
Authors: Gormally Michael , Repetto Matteo , Jee Justin , Chang Jason C. , Selenica Pier , Gazzo Andrea , Richards Allison L. , Donoghue Mark , Aghajanian Carol , Reis-Filho Jorge S. , Weigelt Britta , Drilon Alexander E. , Guo Robin 
Published: June 2024

3073 Background: SWI/SNF complexes are regulators of cell lineage and alterations in these proteins occur in >20% of solid tumors with SMARCA4being the most common. SMARCA4 mutations are associated with worse clinical outcomes in various cancer types but are also vulnerable to novel SMARCA2 inhibitors currently being evaluated in clinical trials. We examined SMARCA4 alterations across cancer types to understand their interplay with other genomic abnormalities and clinical consequences. Methods: We analyzed the Memorial Sloan Kettering (MSK) institutional cohort profiled by MSK-IMPACT tumor-normal sequencing. SMARCA4 mutations were annotated based on OncoKB and literature. FACETS resolved zygosity and genomic metrics of complexity including tumor mutational burden (TMB) and fraction genome altered (FGA). The pan-cancer landscape of somatic SMARCA4 mutations was mapped by both category (Class I vs II) and zygosity (mono- vs biallelic). DISCOVER was employed to evaluate mutational signatures and frequency-adjusted co-occurring and mutually exclusive mutations. We then extracted progression-free (PFS) and overall survival (OS) to systemic therapy using natural language processing. Results: We identified 3,385 tumors from 3,049 patients across cancer types with a total 3,965 oncogenic somatic SMARCA4 alterations. Copy number estimation was successful for 2,343 (69%). Non-small cell lung cancer (NSCLC) was the most abundant SMARCA4-altered histology ( n=493, 7.1% of all NSCLC), and the majority (87%) were biallelic. Other common histologies were colorectal ( n=163, 2.9%), bladder ( n=122, 5.5%), uterine ( n=88, 4.3%), pancreatic ( n=81, 3.2%) and esophagogastric ( n=92, 4%). SMARCA4biallelic mutated tumors had higher chromosomal instability compared to WT (FGA = 0.53 vs 0.47; p<0.001), while monoallelic had lower (FGA = 0.3; p<0.001). Monoallelic SMARCA4 altered tumors had a higher TMB (10.5) than both WT (4.4) and biallelic cancers (6.1; p<0.001). Monoallelic and biallelic SMARCA4 cancers exhibited distinct mutational signatures in most tumor types. Patients with biallelic SMARCA4 mutations had worse outcomes with both immune checkpoint blockade (ICB) and platinum chemotherapy across in certain tumor types, whereas monoallelic uterine cancers were associated with improved outcomes with ICB. Conclusions: This pan-cancer clinicogenomic analysis demonstrates that monoallelic and biallelic SMARCA4-mutated tumors have distinguishable genomic features. In addition, biallelic SMARCA4 alterations correlated with poor outcomes across different cancer-types and classes of therapy, while improved outcomes to ICB in monoallelic SMARCA4alterations were potentially due to higher representation of MSI-H tumors in this subset. Our findings suggest SMARCA4 zygosity may be important biomarkers for ongoing clinical trials in SMARCA4-deficient tumors.