Identification of genetic collaborators in cancer with a brca2-mutant zebrafish model

项目摘要/摘要 癌症的遗传复杂性阻碍了癌症发生过程中关键基因合作者的识别。 已知的癌症相关基因的可遗传突变，如BRCA2，与癌症风险密切相关。 然而，躯体获得性突变极大地促进了癌症的进展。这些附加内容 突变通常是通过扩增和缺失事件(拷贝数改变；CNA)产生的。中央新闻社 可以跨越大的基因组区域并扰乱许多基因，这阻碍了癌症驱动因素的识别。通过 在动物模型(如斑马鱼)中定义与复发癌症相关的CNA，并比较这些数据 对于已知的人类癌症中的cna，我们可以利用物种间基因组结构的差异来识别 反复扰乱这两个物种癌症的基因。因此，这种方法将新颖、保守、 在斑马鱼模型中可以很容易地评估其潜在影响的候选驱动基因 致癌。这项提议的目标是识别和功能特征保守的基因 在BRCA2相关的人类和斑马鱼癌症中被CNA反复干扰。我们之前已经展示了 人类和斑马鱼BRCA2相关癌症之间的遗传相似性，包括协同作用 TP53在BRCA2相关癌变中的作用及BRCA2和/或TP53野生型等位基因的缺失 癌症。我们的中心假设是，在BRCA2中协作的新的、保守的候选驱动基因- 人类和斑马鱼的比较基因组学分析将揭示相关的致癌机制 BRCA2相关癌症。斑马鱼中这些候选基因的活体特征将提供洞察力 研究它们如何调节与癌症发展直接相关的细胞事件，并将指导启动 稳定的转基因和突变斑马鱼品系，用于未来的致癌研究。我们的长期目标是 确定关键保守的组合基因中断和导致癌症的新分子途径 进步。这位K01研究职业生涯奖获得者是DVM/博士。拥有董事会认证的科学家 兽医解剖病理学。K01研究项目是在北卡罗来纳州立大学进行的， 兽医学院(1-3年级)，由Robert Smart博士、Matthew Breen博士和 杰弗里·约德博士，目前正在俄亥俄州立大学兽医学院表演 在拉梅什·甘朱博士(俄亥俄州立大学综合癌症中心)的指导下，并继续指导 斯马特博士、布林博士和约德博士。候选人致力于生物医学研究的职业生涯，并寻求 由该研究和职业发展提供的额外培训、指导和受保护的研究时间 计划帮助她过渡到独立的学术生涯。

Project Summary/Abstract The genetic complexity of cancers impedes identification of key genetic collaborators in carcinogenesis. Heritable mutations in known cancer-associated genes, such as BRCA2, are strongly linked to cancer risk. However, somatically acquired mutations contribute significantly to cancer progression. These additional mutations are often generated through amplification and deletion events (copy number alterations; CNA). CNA can span large genomic regions and disrupt numerous genes, which impedes identification of cancer drivers. By defining recurrent cancer-associated CNA in an animal model such as the zebrafish, and comparing these data to known CNA in human cancers, we can use differences in genomic architecture between species to identify recurrently disrupted genes in cancers from both species. This approach thus identifies novel, conserved, candidate driver genes that can be easily assessed in the zebrafish model for their potential to impact carcinogenesis. The goal for this proposal is to identify and functionally characterize conserved genes that are recurrently disrupted by CNA in BRCA2-associated human and zebrafish cancers. We have previously shown genetic similarities between human and zebrafish BRCA2-associated cancers, which include the collaborative role for tp53 in brca2-associated carcinogenesis and the loss of the wild type alleles for brca2 and/or tp53 in cancers. Our central hypothesis is that novel, conserved, candidate driver genes that collaborate in BRCA2- associated carcinogenesis will be revealed through comparative genomics analyses of human and zebrafish BRCA2-associated cancers. In vivo characterization of these candidate genes in zebrafish will provide insight into how they modulate cellular events of direct relevance to cancer development, and will guide initiation of stable transgenic and mutant zebrafish lines for use in future carcinogenesis studies. Our long-term goal is to define key conserved combinatorial gene disruptions and novel molecular pathways that drive cancer progression. This K01 Research Career Award recipient is a DVM/PhD. scientist with board certification in Veterinary Anatomic Pathology. The K01 research project was performed at North Carolina State University, College of Veterinary Medicine (years 1-3), under the mentorship of Dr. Robert Smart, Dr. Matthew Breen, and Dr. Jeffrey Yoder, and is currently being performed at the Ohio State University, College of Veterinary Medicine under the mentorship of Dr. Ramesh Ganju (OSU Comprehensive Cancer Center) and continued mentorship of Drs. Smart, Breen, and Yoder. The candidate is committed to a career in biomedical research, and seeks the additional training, mentorship, and protected research time provided by this research and career development plan to facilitate her transition to an independent academic career.