The Pan-tumor Landscape, Allelic Status, and Genomic Complexity of SMARCA4 Alterations

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Abstract
Purpose: The clinical implications of distinct SMARCA4 alteration classes remain incompletely defined. We performed a pan-cancer analysis to characterize SMARCA4 mutation classes and their associations with allelic status, genomic context, and therapeutic outcomes. Experimental Design: We analyzed 68,920 tumor–normal paired samples sequenced with the MSK-IMPACT next-generation sequencing assay between 2015 and 2023. We curated oncogenic or likely oncogenic SMARCA4 alterations using OncoKB and classified them based on prior functional and structural literature. Allele-specific copy number, ploidy, fraction of genome altered, loss of heterozygosity, and whole-genome doubling were calculated. Clinical outcomes were evaluated in selected tumor cohorts treated with platinum-based therapy or immune checkpoint blockade. Results: SMARCA4 alterations were most frequent in thymic epithelial tumors (10.7%), non–small cell lung cancer (7.1%), bladder cancer (5.6%), and cervical cancer (5%). Class 1 and 2 alterations occurred in 2.9% and 0.7% of tumors, respectively. Distinct patterns of genomic complexity, co-occurring alterations, and mutational signatures were observed across tumor types based on SMARCA4 alteration allelic state and class. In a phase I trial of the BRM degrader PRT3789, patients with monoallelic class 2 SMARCA4 alterations and preserved BRG1 expression saw clinical benefit, including 1 who attained a complete response. Conclusions: SMARCA4 alteration class and allelic status define biologically and clinically distinct subsets of tumors. These findings support incorporating allelic status and functional mutation class into patient selection strategies for emerging BRM-targeted therapies.
Funding Information
  • National Institutes of Health (P30 CA008748)
  • National Institutes of Health (P01 CA129243)
  • Nonna’s Garden
  • LUNGevity Foundation
  • Happy Lungs
  • The Squeri Grant for Drug Development
  • National Institutes of Health (1R01CA251591)
  • National Institutes of Health (1R01CA273224)
  • Cycle for Survival
  • Breast Cancer Research Foundation

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