How do genome alterations cause human lung cancer?

 描述（由申请人提供）：肺癌占更多的癌症相关的死亡，每年在全球范围内，比未来三个最流行的癌症的总和;可悲的是，超过50%的患者在诊断后一年内死亡。我们的实验室为了解非小细胞肺癌的基因组基础做出了重大贡献，非小细胞肺癌占肺癌的85%。作为癌症基因组学研究前沿的团队之一，我们和其他人已经发现了肺腺癌和鳞状细胞癌中的许多主要基因组改变，具有深远的临床意义。这些研究促进了分子靶向治疗的发展，并了解了患者对分子靶向治疗的反应，特别是我们证明了EGFR基因内的突变决定了肿瘤对抗EGFR药物吉非替尼的反应。虽然我们现在可以为患者提供比几年前想象的更多的治疗选择，但疾病进展不可避免地加剧，强调需要开发不同的更新方法来治疗这一祸害。答案可能在于许多主要的，但仍然知之甚少，基因组畸变驱动这些癌症的发病机制。在这方面，一些最令人困惑的基因组事件涉及（i）谱系特异性癌基因的局灶性扩增的作用，例如我们在肺腺癌中发现的NKX 2 -1和在肺鳞状细胞癌中发现的SOX 2，（ii）在肺腺癌中发现剪接因子基因的体细胞突变，特别是U2 AF 1和RBM 10;和（iii）在这些癌症和大多数其他癌症中观察到频繁的大规模染色体改变，例如染色体臂或甚至整个染色体的增加或丢失。在肺腺癌和鳞状细胞癌中有了这些发现后，我们现在打算集中精力描绘这些复杂而神秘的基因组畸变促进肿瘤发生的机制。在这里，我们将利用新的，易于处理的基因组工程方法，在基于细胞和小鼠模型系统中模拟这些基因组事件。我们还将采用全方位的功能和系统方法，如转录组学，蛋白质组学，遗传筛选和依赖性分析，以揭示这种改变的生物学相关性。通过从所有可能的角度解决肺癌生物学中这些具有挑战性的问题，我们预计我们将全面了解这些神秘的基因组改变如何促进肺癌的发病机制，从而为新的治疗方法提供信息。

 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.