Survival associated with mutations in SWI/SNF chromatin remodeling complex genes.

3643 Background: The SWI/SNF (SWitch/Sucrose NonFermentable) chromatin remodeling complex (CRC) - a combinatorial assembly of products from multiple genes - alters histone/DNA interactions and thereby impacts transcription, DNA replication/repair, and cell division. Studies suggest that over 20% of human cancers contain mutations in at least one SWI/SNF gene, implying that it is the most highly mutated CRC in human cancer. To address existing knowledge gaps, we sought to evaluate the association between SWI/SNF mutations and overall survival (OS). Methods: We identified adult cancer patients who consented to have OncoPanel testing (Dana-Farber/Brigham & Women’s Hospital’s next generation sequencing platform) from June 2013-August 2019. These data were merged with institutional electronic health records and National Death Index vital status. We determined mutation frequency and co-occurrence for the nine SWI/SNF genes included in OncoPanel (ARID1A, ARID1B, ARID2, BCL11B, PBRM1, SMARCA4, SMARCB1, SMARCE1, and SS18). We assessed the association between mutation and OS (from time of OncoPanel testing) for cancers with at least 500 analyzed and 20 mutated cases, controlling for age and TP53 status. Exploratory analyses were conducted using cBioPortal and SAS (no multiple comparison adjustment). Results: Among 25,434 samples from 24,648 patients, a mutation in at least one evaluated SWI/SNF gene was identified in 26% of cases (ARID1A 10.5%, ARID1B 7.2%, SMARCA4 5.5%, PBRM1 4.9%, ARID2 4.8%, BCL11B 3.5%, SMARCE1 1.1%, SMARCB1 1.0%, and SS18 0.7%). The most frequently mutated cancers included small bowel (52%), endometrial (49%), ampullary (48%) and bladder (45%). Co-occurrence was common (30 of 36 potential gene-pairs), with the largest associations (odds ratio; all P < .05) seen for SMARCB1:BCL11B (4.19), ARID1B:BCL11B (3.87), ARID2:BCL11B (3.85), and SMARCA4:BCL11B (3.78). Associations between having a mutation and OS were seen for the following cancers/genes (odds ratio; all P < .05): ARID1A (colorectal 0.72, pancreatic 1.46), ARID1B (melanoma 0.32), SMARCA4 (esophagogastric 1.48, non-small cell lung 1.89, ovarian 0.43), SMARCB1 (non-small cell lung 2.04), and SS18 (soft tissue sarcoma 2.06). Conclusions: Mutations in SWI/SNF genes are widespread, with mutation rates varying by cancer type. Co-occurrence was common, especially with BCL11B. Associations with OS were both favorable and unfavorable, with variability seen by gene and cancer type. Future research should explore the mechanisms by which mutations in SWI/SNF genes influence treatment response/OS.