The spectrum of SWI/SNF mutations, ubiquitous in human cancers.
SWI/SNF is a multi-subunit chromatin remodeling complex that uses the energy of ATP hydrolysis to reposition nucleosomes, thereby modulating gene expression. Accumulating evidence suggests that SWI/SNF functions as a tumor suppressor in some cancers. However, the spectrum of SWI/SNF mutations across human cancers has not been systematically investigated. Here, we mined whole-exome sequencing data from 24 published studies representing 669 cases from 18 neoplastic diagnoses. SWI/SNF mutations were widespread across diverse human cancers, with an excess of deleterious mutations, and an overall frequency approaching TP53 mutation. Mutations occurred most commonly in the SMARCA4 enzymatic subunit, and in subunits thought to confer functional specificity (ARID1A, ARID1B, PBRM1, and ARID2). SWI/SNF mutations were not mutually-exclusive of other mutated cancer genes, including TP53 and EZH2 (both previously linked to SWI/SNF). Our findings implicate SWI/SNF as an important but under-recognized tumor suppressor in diverse human cancers, and provide a key resource to guide future investigations.
Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
A Hunter
AH
Shain
Jonathan R
JR
Pollack
D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D057225:Data Mining; D059472:Exome; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D002868:Chromosomal Proteins, Non-Histone; C445179:SWI-SNF-B chromatin-remodeling complex; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53