Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
Nat Genet. 2013 Jun;45(6):592-601. doi: 10.1038/ng.2628. Epub 2013 May 5.
Subunits of mammalian SWI/SNF (mSWI/SNF or BAF) complexes have recently been implicated as tumor suppressors in human malignancies. To understand the full extent of their involvement, we conducted a proteomic analysis of endogenous mSWI/SNF complexes, which identified several new dedicated, stable subunits not found in yeast SWI/SNF complexes, including BCL7A, BCL7B and BCL7C, BCL11A and BCL11B, BRD9 and SS18. Incorporating these new members, we determined mSWI/SNF subunit mutation frequency in exome and whole-genome sequencing studies of primary human tumors. Notably, mSWI/SNF subunits are mutated in 19.6% of all human tumors reported in 44 studies. Our analysis suggests that specific subunits protect against cancer in specific tissues. In addition, mutations affecting more than one subunit, defined here as compound heterozygosity, are prevalent in certain cancers. Our studies demonstrate that mSWI/SNF is the most frequently mutated chromatin-regulatory complex (CRC) in human cancer, exhibiting a broad mutation pattern, similar to that of TP53. Thus, proper functioning of polymorphic BAF complexes may constitute a major mechanism of tumor suppression.
哺乳动物 SWI/SNF（mSWI/SNF 或 BAF）复合物的亚基最近被认为是人类恶性肿瘤中的肿瘤抑制因子。为了全面了解它们的参与程度，我们对内源性 mSWI/SNF 复合物进行了蛋白质组学分析，鉴定出了几个新的、专门的、稳定的亚基，这些亚基在酵母 SWI/SNF 复合物中没有发现，包括 BCL7A、BCL7B 和 BCL7C、BCL11A 和 BCL11B、BRD9 和 SS18。将这些新成员纳入其中，我们确定了 mSWI/SNF 亚基在原发性人类肿瘤外显子组和全基因组测序研究中的突变频率。值得注意的是，在 44 项研究报告的所有人类肿瘤中，有 19.6%的肿瘤存在 mSWI/SNF 亚基的突变。我们的分析表明，特定的亚基在特定的组织中可以预防癌症。此外，影响一个以上亚基的突变，这里定义为复合杂合性，在某些癌症中很常见。我们的研究表明，mSWI/SNF 是人类癌症中最常发生突变的染色质调节复合物（CRC），表现出与 TP53 相似的广泛突变模式。因此，多态性 BAF 复合物的正常功能可能构成肿瘤抑制的主要机制。
