Loss of function of SWI/SNF chromatin remodeling genes leads to genome instability of human lung cancer

Abstract

Abstract. SWI/SNF chromatin remodeling complexes are frequently mutated in a variety of human cancers. We investigated the mutation incidence and the role of mSWI/SNF (BAF) complexes in human lung cancer. In the present study, we analyzed somatic mutations of BAF complexes and other driver mutated genes of lung carcinoma deposited in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. BAF complexes were mutated in 282 of 803 (35.12%) lung carcinoma samples analyzed, ranking second to TP53. Significantly, BAF-mutated samples exhibited more genomic mutations than BAF wild-type ones. Moreover, a significant positive correlation existed between the BAF mutations and overall genomic mutations in these lung carcinoma samples (P<0.001, Pearson's correlation analysis). Specifically, the mutant-typing of 6 BAF genes, SMARCA4, ARID2, ARID1B, BCL11A, BCL11B and BRD9 was associated with more overall mutations in the lung carcinoma samples. A mutation reporter system was developed by means of the establishment of stable cell sublines with slippage-luciferase transcript in a lung adenocarcinoma cell line, Calu-3. SMARCA4, the most frequently mutated BAF gene in lung cancer, was stably knocked down by pSUPER constructs carrying short hairpin RNA (shRNA). Mutation ratios determined from the mutation reporters of Calu-3 cells were significantly increased upon stable SMARCA4 knockdown. We demonstrated that genetic mutations of BAF complexes lead to genome instability of lung carcinoma. Therefore, BAF complexes play an important role in maintaining genome stability in human lung cancer.

Mutations in ARID2 are associated with intellectual disabilities

“…A recent study also shows that the PBAF remodeling complex is important for doublestrand breaks (DSBs)-induced transcriptional silencing and promotes repair of a subset of DNA DSBs at early time points [48]. ARID2 has been recently identified as a key cancer gene for hepatocellular carcinoma [49,50], melanoma [51,52], and lung cancer [53]. Recently, a missense mutation R314C in ARID2 was reported in an individual with autism [54].…”

Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis

“…Dysfunction of several genes from 2p15p16.1 was also associated with genomic instability (BCL11A, ref. 27; USP34, ref. 26; and XPO1 ref.…”

“…USP34, a deubiquitinase, was also reported to be associated with the NF-κB pathway (24) in addition to having a role in the Wnt signaling pathway (25) and genomic stability (26). Finally, BCL11A, a Kruppellike transcription factor that represses transcription, is a member of the Brahma-related gene 1 (BRG1) associated factors (BAF) complex involved in the modification of chromatin structure and also has a role in regulating genomic stability (27), polarity, and migration of cortical upper layer neurons (28), as well as expression of fetal hemoglobin (4).…”

Facilitation of base excision repair by chromatin remodeling

“…In addition, BRG1 is known to bind or regulate the expression of proteins involved in cancer development, such as MYC [48], P53 [49], BRCA1, beta-catenin, LKB1, FANCA and RB [50]. Furthermore, it has been recently found that loss of SWI/SNF leads to genome instability in human lung cancer [51]. …”