Abstract A38: The role of MGA loss-of-function mutations in lung adenocarcinomas

MYC activation promotes tumorigenesis in a wide range of tissues. The Cancer Genome Atlas project has recently reported that MGA, encoding a potential suppressor of MYC activity, is significantly mutated in lung adenocarcinomas and the majority of mutations are loss-of-function. Roughly 10% of lung adenocarcinoma cases acquire either MGA loss-of-function mutations or homozygous deletions. Employing functional genomics methodologies, we aimed to characterize the role of MGA mutations in lung adenocarcinoma, with an emphasis on studying their involvement in modulating MYC activity. Using CRISPR knockout technologies, we showed that MGA inactivation induces cellular transformation of primary lung epithelium cells AALE, suggesting that MGA acts as a tumor suppressor. In addition, by performing chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) assays, we showed that MGA competes with MYC for a subset of DNA-binding sites and represses the expression of genes nearby. Finally, we revealed that the gene repression function of MGA is due to its association with the HDAC1/2 complex. The discovery of MGA mutations defines a new pathway in lung adenocarcinoma: the MYC/MAX/MGA pathway. Our study not only illuminates the activity MGA mutant lung adenocarcinomas but also those tumors with amplifications of MYC. Citation Format: Xiaoyang Zhang, Joshua Francis, Charles Lin, Peter Rahl, James Bradner, Richard Young. The role of MGA loss-of-function mutations in lung adenocarcinomas. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A38.