"Comparative gene resequencing in mouse cancer models"

描述（由申请人提供）：本职业发展提案将支持大卫麦克法登博士在小鼠癌症模型和基因组学方面的培训，由泰勒杰克斯博士指导，并得到合作者迈耶森博士、汉农博士、兰德博士和盖兹博士的支持。候选人McFadden博士接受过小鼠遗传学、内科学和内分泌学方面的培训，并从事甲状腺癌患者护理的临床实践。导师Jacks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。Meyerson，Hannon，Lander和Getz博士在人类肺腺癌遗传学，基因组学和生物信息学方面拥有丰富的专业知识。在这个独特的科学环境中，McFadden博士将有机会接受癌症生物学和基因组学方面的培训，将小鼠癌症模型与尖端遗传技术相结合，以确定治疗人类癌症的新靶点。大规模并行DNA测序方法的发展推动了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的定义更具挑战性。已经开发并利用精心构建的人类癌症小鼠模型来仔细表征肿瘤发生的所有阶段，包括肿瘤起始、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是从头开始已知的，但是在从增生到侵袭性肿瘤的进展期间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与人类癌症中检测到的基因表达特征和DNA拷贝数特征重叠的基因表达特征和DNA拷贝数特征，这表明小鼠和人类之间共享对癌细胞施加的选择性压力。这些研究证明了跨物种比较的价值，以确定功能重要的驱动基因，指导组成人类癌症进展的不同细胞过程。在这个为期5年的提案中，我们将从肺腺癌小鼠模型中生成大规模测序数据集，以识别肿瘤演变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，以排名候选基因和最感兴趣的途径，并使用基因工程小鼠模型和人类癌细胞精确表征这些改变的功能作用。我们的初步数据表明，这种方法是可行的。我们已经建立了一个小鼠肺腺癌组织库，包括晚期、高级别小鼠肿瘤、细胞系和转移瘤，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。使用这种新技术，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。 公共卫生相关性：肿瘤进展为侵袭性和转移性肿瘤是大多数癌症死亡的原因。这项研究利用小鼠癌症模型中的大规模DNA测序和比较基因组学来识别和剖析控制肿瘤进展的基因的功能作用。我们预计这项工作将确定治疗侵袭性和转移性癌症的新靶点。 个别评审员的书面评论和标准评分在下面的“评论”部分以基本上未经编辑的形式提供。请注意，这些评论和标准评分是在会议之前准备的，在审查会议上进行任何讨论之后可能没有进行修订。上文“讨论的简历和摘要”部分总结了委员会的最终意见。

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.