The genetic alterations involved in the development lung adenocarcinoma (ADC) have been widely characterized allowing the identification of the most frequent oncogenes or tumor suppressor genes linked to this malignancy. Most studies have focus on proliferation pathway, anti-apoptotic factors or cell cycle alterations. Here we show that alterations in chromatin remodeling complexes are frequent in lung ADC. Chromatin structure plays a key role in the regulation of tissue-specific gene expression during development and differentiation therefore it is not surprising that proteins implicated in remodeling complexes play a role in cancer development. For example, mutations have been found in genes belonging to the SWI/SNF complex in different tumors. In lung cancer BRG1 knockout was shown to potentiate tumor development and mutations were recently identified in tumors by the use of a very sensitive method: massive parallel DNA pyrosequencing that suggests the presence of the alteration in cell subclones. In the course of identifying novel chromatin remodeling complex genes implicated in lung ADC development we analyzed a series of 82 lung adenocarcinomas by SNP array and looked for the presence of homozygous deletions on the entire genome. Three regions of homozygous deletions in known tumor suppressor genes CDKN2A, FHIT and PTEN and in JARID2, which is involved in chromatin remodeling, were found in more than 2 samples. Another ARID-domain containing gene; ARID2 was found deleted in one sample and we therefore decided to screen both ARID-domain genes for mutations by direct sequencing on cryopreserved tumor tissues. One missense somatic mutation was found in JARID2 and 6/82 tumors had ARID2 alterations predicted to inactivate the protein in at least 4 out of 6 samples. Indeed 3 mutations were frameshift or non-sense, one specimen had a homozygous deletion and 4 tumors demonstrated loss of heterozygosity associated to the mutation. Our results indicate that ARID2 inactivation is a common feature of lung cancer development and provide new insight on the impact of chromatin remodeling alteration in lung ADC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5121. doi:1538-7445.AM2012-5121