"Comparative gene resequencing in mouse cancer models"

描述（由申请人提供）：本职业发展计划将支持David McFadden博士在taylor Jacks博士的指导下进行小鼠癌症模型和基因组学方面的培训。迈耶森，汉农，兰德和盖兹。候选人麦克法登博士接受过小鼠遗传学、内科和内分泌学方面的培训，并致力于甲状腺癌患者的临床护理。导师杰克博士是癌症研究领域的国际领导者，专注于开发和使用复杂的小鼠癌症模型。Drs。Meyerson, Hannon， Lander和Getz带来了人类肺腺癌遗传学，基因组学和生物信息学方面的丰富专业知识。在这个独特的科学环境中，麦克法登博士将有机会在癌症生物学和基因组学方面进行培训，以便将小鼠癌症模型与尖端基因技术相结合，以确定人类癌症治疗的新靶点。大规模平行DNA测序方法的发展推动了对人类癌症基因组的详细描述。然而，特定突变与癌症表型的功能相关性更具有挑战性。精心构建的人类癌症小鼠模型已经被开发出来，并用于仔细表征肿瘤发生的各个阶段，包括肿瘤的起始、进展和转移。虽然在这些模型中负责肿瘤诱导的基因工程突变从头开始是已知的，但从增生到侵袭性肿瘤的进展过程中获得的突变谱在很大程度上仍然未知。研究表明，精心构建的小鼠模型显示出基因表达特征和DNA拷贝数谱与人类癌症中检测到的基因表达特征和DNA拷贝数谱重叠，这表明施加在癌细胞上的选择压力在小鼠和人类之间是共享的。这些研究证明了跨物种比较的价值，以确定指导构成人类癌症进展的各种细胞过程的功能重要驱动基因。在这项为期5年的计划中，我们将从肺腺癌小鼠模型中生成大规模测序数据集，以确定肿瘤进化过程中获得的点突变。我们将进行跨物种比较研究和途径分析，对最感兴趣的候选基因和途径进行排序，并使用基因工程小鼠模型和人类癌细胞精确地表征这些改变的功能作用。初步数据表明，这种方法是可行的。我们已经建立了一个由晚期、高级别小鼠肿瘤、细胞系和转移瘤组成的小鼠肺腺癌组织库，并开发了一个基于杂交的富集平台，用于捕获和测序癌症相关基因。利用这项新技术，我们对小鼠肺腺癌细胞系进行了测序，并鉴定了肿瘤进展过程中获得的体细胞突变。

DESCRIPTION (provided by applicant): This Career Development proposal will support the training of Dr. David McFadden in mouse cancer models and genomics under the mentorship of Dr. Tyler Jacks with support from collaborators Drs. Meyerson, Hannon, Lander, and Getz. The candidate, Dr. McFadden, is trained in mouse genetics, internal medicine and endocrinology with a clinical practice devoted to the care of thyroid cancer patients. The mentor, Dr. Jacks, is an international leader in cancer research with a focus on the development and use of sophisticated mouse cancer models. Drs. Meyerson, Hannon, Lander, and Getz bring a wealth of expertise in human lung adenocarcinoma genetics, genomics, and bioinformatics. In this unique scientific environment, Dr. McFadden will have the opportunity to train in cancer biology and genomics in order to blend mouse cancer models with cutting edge genetic technology in order to identify novel targets for treatment in human cancer. The development of massively parallel DNA sequencing methodologies has fueled the detailed description of human cancer genomes. However, the functional relevance of specific mutations to the cancer phenotype has been more challenging to define. Carefully constructed mouse models of human cancer have been developed and utilized to carefully characterize all stages of tumorigenesis, including tumor initiation, progression, and metastasis. Although the genetically engineered mutations responsible for tumor induction in these models are known ab initio, the spectrum of mutations acquired during progression from hyperplasia to invasive neoplasm remains largely unknown. Studies have demonstrated that carefully constructed mouse models exhibit gene expression signatures and DNA copy number profiles that overlap with those detected in human cancers, suggesting that the selective pressures exerted on cancer cells are shared between mice and humans. These studies demonstrate the value of cross-species comparisons to identify functionally important driver genes that direct the diverse cellular processes that compose human cancer progression. Over this 5-year proposal, we will generate large-scale sequencing datasets from a mouse model of lung adenocarcinoma to identify the point mutations acquired during tumor evolution. We will perform cross- species comparative studies and pathway analyses to rank candidate genes and pathways of most interest, and precisely characterize the functional role of these alterations using genetically engineered mouse models and human cancer cells. Our preliminary data demonstrate that this approach is feasible. We have generated a murine lung adenocarcinoma tissue bank consisting of advanced, high-grade murine tumors, cell lines, and metastases and developed a hybridization-based enrichment platform for the capture and sequencing of cancer-relevant genes. Using this novel technology, we have sequenced murine lung adenocarcinoma cell lines and identified somatic mutations acquired during tumor progression. PUBLIC HEALTH RELEVANCE: Tumor progression to invasive and metastatic tumors is responsible for most cancer deaths. This study utilizes large-scale DNA sequencing in mouse cancer models and comparative genomics to identify and dissect the functional role of genes that control tumor progression. We anticipate this work will identify new targets for treatment of invasive and metastatic cancers. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" section above summarizes the final opinions of the committee.