How do genome alterations cause human lung cancer?

 描述(申请人提供)：肺癌每年在全球范围内造成的与癌症相关的死亡人数超过了接下来三种最常见癌症的总和；可悲的是，超过50%的患者在确诊后一年内死亡。我们的实验室在了解非小细胞肺癌的基因组基础方面做出了重大贡献，非小细胞肺癌占肺癌的85%。作为癌症基因组学研究的前沿之一，我们等人在肺腺癌和鳞癌中发现了许多主要的基因组变化，具有深刻的临床意义。这些研究导致了分子靶向治疗的发展和对患者反应的理解，特别是我们证明，EGFR基因内的突变决定了肿瘤对抗EGFR药物吉非替尼的反应。尽管我们现在可以为患者提供比几年前所能想象的更多的治疗选择，但疾病的恶化不可避免地接踵而至，突显出需要开发不同的新方法来治疗这一祸害。答案可能在于驱动这些癌症发病机制的许多主要的、但仍然鲜为人知的基因组异常。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焦点扩增所起的作用，例如我们在肺腺癌中发现了NKX2-1基因，在肺鳞癌中发现了SOX2基因，(Ii)在肺腺癌中发现了剪接因子基因的体细胞突变，尤其是U2AF1和RBM10基因；以及(Iii)在这些癌症以及大多数其他癌症中观察到了频繁的大规模染色体变化，例如染色体臂甚至整个染色体的增减。在肺腺癌和鳞癌中取得这些发现后，我们现在打算重点描述这些复杂而神秘的基因组异常促进肿瘤发生的机制。在这里，我们将利用新的、易处理的基因组工程方法，在基于细胞的系统和小鼠模型系统中对这些基因组事件中的每一个进行建模。我们还将采用全面的功能和系统方法，如转录组、蛋白质组学、基因筛查和相关性分析，以揭示这种变化的生物学相关性。通过从所有可能的角度解决肺癌生物学中的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变化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.