Recurrent inactivating mutations of ARID2 in non-small cell lung carcinoma

Abstract

In eukaryotic cells, DNA is packaged into chromatin and this compact storage in the nucleus promotes transcriptional repression of genes. Chromatin remodeling complexes such as the SWI/SNF complex are involved in making DNA accessible to transcription factors and thereby are implicated in the regulation of gene expression. Mutations and altered expression of chromatin remodeling complex genes have been described in cancer cells. Indeed, non-small cell lung cancer cell lines have been shown to harbor mutations in SMARCA4 (BRG1), a member of the SWI/SNF complex, but evidence has been less clear in primary tumors. Recently, inactivating mutations in AT-rich interaction domain 2 (ARID2) were found in liver cancer related to HCV infection and in melanoma. Here, we explored, using a genome-wide strategy and subsequent sequencing of targeted genes, whether chromatin remodeling is implicated in primary lung adenocarcinoma. Two genes were individualized from the genome screening as homozygously deleted in a set of samples: JARID2 and ARID2. Subsequent analysis of the entire coding sequences showed that ARID2 loss-of-function mutations were found in 5% of nonsmall cell lung cancers, thereby constituting one of the most frequently mutated genes in this cancer type after TP53, KRAS, EGFR, CDKN2A and STK11. What's new? Chromatin plays a key role in tissue-specific gene expression during development and differentiation and is often corrupted in cancer cells. The authors focused on the identification of mutations in chromatin-remodeling genes in non-small cell lung carcinoma, the most frequent type of lung cancer. They identified several inactivating mutations of ARID2, a subunit of the SWI/SNF chromatin-remodeling complex. With a loss-of-function mutation rate of 5%, ARID2 is one of the most frequently mutated genes in this cancer type, after TP53, KRAS, EGFR, CDKN2A and STK11. These results underscore the central role of chromatin in curbing cancer and implicate ARID2 as a new tumor suppressor in lung cancer development. Copyright © 2012 UICC.