Abstract
BackgroundAlterations in genes encoding chromatin regulatory proteins are prevalent in cancers and may confer oncogenic properties and molecular changes linked to therapy resistance. However, the impact of copy number alterations (CNAs) of the SWItch/Sucrose NonFermentable (SWI/SNF) complex on the oncogenic and immunologic properties has not been systematically explored across human cancer types.MethodsWe comprehensively analyzed the genomic, transcriptomic and clinical data of The Cancer Genome Atlas (TCGA) dataset across 33 solid cancers.ResultsCNAs of the SWI/SNF components were identified in more than 25% of all queried cancers, and tumors harboring SWI/SNF CNAs demonstrated a worse overall survival (OS) than others in several cancer types. Mechanistically, the SCNA events in the SWI/SNF complex are correlated with dysregulated genomic features and oncogenic pathways, including the cell cycle, DNA damage and repair. Notably, the SWI/SNF CNAs were associated with homologous recombination deficiency (HRD) and improved clinical outcomes of platinum-treated ovarian cancer. Furthermore, we observed distinct immune infiltrating patterns and immunophenotypes associated with SWI/SNF CNAs in different cancer types.ConclusionThe CNA events of the SWI/SNF components are a key process linked to oncogenesis, immune infiltration and therapeutic responsiveness across human cancers.
Highlights
Combinations of somatic genetic alterations, including single base substitutions, translocations, and copy number alterations (CNAs) in essential genes and pathways can lead to the development of cancer [1, 2]
Widespread CNAs of SWItch/Sucrose NonFermentable (SWI/SNF) complex components across human cancers We first analyzed the prevalence of copy number variations (CNVs) in genes encoding the subunits of the SWI/SNF complex, such as the BRG1/BRM- associated factor complexes (cBAF), polybromo- associated BAF (PBAF), non-canonical BAF (ncBAF), and shared subunits
We identified that the CNA events of the SWI/SNF pathway existed in 26% of all queried cancers, ranging from 0.4 to 6% (Fig. 1A and Figure S1)
Summary
Combinations of somatic genetic alterations, including single base substitutions, translocations, and copy number alterations (CNAs) in essential genes and pathways can lead to the development of cancer [1, 2]. Previous studies have revealed the high prevalence of alterations in genes encoding chromatin regulatory proteins, implicating them as key regulators in the pathogenesis of human cancers [5]. Among these genetic changes, alterations in genes encoding subunits of SWI/ SNF (SWItch/Sucrose NonFermentable), one of the ATPdependent chromatin remodeling complexes, are present in more than 20% of all human cancers [6, 7]. Genes encoding the subunits of the SWI/SNF complex have emerged as broadly mutated in human malignancies, the SCNA events of the complex and the associated clinical relevance has not been well-characterized. The impact of copy number alterations (CNAs) of the SWItch/Sucrose NonFermentable (SWI/SNF) complex on the oncogenic and immunologic properties has not been systematically explored across human cancer types
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