How do genome alterations cause human lung cancer?

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 DESCRIPTION (provided by applicant): Lung cancer accounts for more cancer-related deaths worldwide, per year, than the next three most prevalent cancers combined; sadly, more than 50% of patients die within a year of diagnosis. Our lab has made significant contributions to understanding the genomic underpinnings of non-small cell lung cancer, which accounts for ~85% of lung cancers. As one of the groups at the forefront of cancer genomics research, we and others have uncovered many major genome alterations in lung adenocarcinomas and squamous cell carcinomas, with profound clinical implications. These studies have resulted in the development of-and understanding of patient response to-molecularly targeted therapies, notably our demonstration that mutations within the EGFR gene dictate tumor response to the anti-EGFR drug, gefitinib. Although we can now offer patients many more therapeutic options than imaginable even a few years ago, disease progression inevitably ensues, underscoring the need for development of different and newer approaches to treating this scourge. The answer may lie in the numerous major, but still poorly understood, genomic aberrations that drive pathogenesis of these cancers. Some of the most perplexing genomic events in this regard relate to (i) the role of focal amplification of lineage-specific oncogenes, such as we discovered for NKX2-1 in lung adenocarcinomas and SOX2 in lung squamous cell carcinomas, (ii) the finding of somatic mutations in splicing factor genes, specifically U2AF1 and RBM10, in lung adenocarcinoma; and (iii) the observation of frequent large-scale chromosomal alterations such as gains or losses of chromosomal arms or even entire chromosomes, in these-and indeed most other-cancers. Having made these discoveries in lung adenocarcinomas and squamous cell carcinomas, we now intend to focus on delineating the mechanisms through which these complex and mysterious genomic aberrations promote oncogenesis. Here, we will take advantage of new, tractable genome engineering approaches to model each of these genomic events in both cell-based and mouse model systems. We will also employ a full spectrum of functional and systematic methodologies such as transcriptomic, proteomic, genetic screening and dependency analyses to uncover the biological relevance of such alterations. By addressing these challenging questions in lung cancer biology from all possible angles, we anticipate that we will gain a comprehensive understanding of how these mysterious genome alterations fuel pathogenesis of lung cancers, thereby informing novel therapeutic approaches.