High-resolution genome-wide mapping of structural mutations in prostate cancer

描述(申请人提供)：摘要：作为一名拥有结构生物学博士学位的内科医生，我的目标是成为一名研究前列腺癌体细胞遗传学的独立研究员，同时保持在肿瘤学方面的少量临床实践。我是Dana-Farber癌症研究所的肿瘤学讲师，在Matthew Meyerson博士的实验室接受培训，并获得哈佛大学和麻省理工学院博德研究所的资源。除了Meyerson博士和其他人的课程作业、会议出席和指导之外，我还提出了一个研究项目，以确定前列腺癌中染色体异常的特征，将它们与癌症进展联系起来，并确定靶向癌基因和肿瘤抑制基因。前列腺癌的特点是它的临床异质性，一些癌症仍然处于惰性状态，另一些癌症需要局部治疗以防止转移和死亡。不幸的是，我们不知道这些差异的遗传基础。了解这一点可能会使标记物的开发能够区分侵袭性和惰性前列腺癌，并可以针对导致进展性疾病的分子变化进行治疗。我们已经开发出利用单核苷酸多态(SNP)阵列在高分辨率和整个基因组中表征前列腺癌染色体异常的技术，包括杂合性丢失(LOH)和拷贝数变化。我们能够以高精度识别已知的癌基因和肿瘤抑制基因靶点，并拥有其他靶区的小而有趣的候选基因列表。在这里，我们建议使用这项技术来解决前列腺癌进展的体细胞遗传学并验证那些基因靶点，有三个特定的目标：1，识别染色体异常，包括LOH和拷贝数变化，在局部和转移性前列腺癌之间的患病率不同；2，识别候选癌基因和肿瘤抑制基因中的点突变和插入/缺失事件，这些突变似乎是这些异常的靶向；3，从功能上验证AIMS 1和2中选定的候选癌基因。相关性：前列腺癌是由于细胞DNA中突变的积累而产生的。我们的目标是识别与其生长和扩散到前列腺外部相关的突变。识别它们可能有助于我们提前识别可能扩散的癌症，并开发治疗它们的方法。

DESCRIPTION (provided by applicant): Summary: As a physician with a PhD in structural biology, I aim to become an independent investigator studying the somatic genetics of prostate cancer while maintaining a small clinical practice in oncology. I am an Instructor in Oncology at the Dana-Farber Cancer Institute, receiving training in the laboratory of Dr. Matthew Meyerson, with additional access to the resources of the Broad Institute of Harvard and MIT. In addition to coursework, conference attendance, and mentoring by Dr. Meyerson and others, I propose a research project to characterize chromosomal aberrations in prostate cancer, relate them to cancer progression, and identify targeted oncogenes and tumor suppressor genes. Prostate cancer is distinguished by its clinical heterogeneity, with some cancers remaining indolent and others requiring local therapy to prevent metastasis and death. Unfortunately, we do not know the genetic bases of these differences. Understanding this may allow development of markers to distinguish between aggressive and indolent prostate cancer, and therapeutics to target the molecular alterations that give rise to progressive disease. We have developed techniques to characterize chromosomal aberrations in prostate cancer, including loss of heterozygosity (LOH) and copy number changes, at high resolution and throughout the genome, using single nucleotide polymorphism (SNP) arrays. We are able to identify known oncogene and tumor suppressor gene targets with high accuracy, and have small and intriguing candidate gene lists for other targeted regions. Here we propose to use this technology to address the somatic genetics of prostate cancer progression and validate those gene targets, with three specific aims: 1, Identify chromosomal aberrations, including LOH and copy number alterations, differing in prevalence between localized and metastatic prostate cancers; 2, Identify point mutations and insertion/deletion events in candidate oncogenes and tumor suppressor genes that appear targeted by these aberrations; and 3, Functionally validate selected candidate oncogenes from Aims 1 and 2. Relevance: Prostate cancer arises due to the accumulation of mutations in the DNA of a cell. We aim to identify mutations associated with its growth and spread outside of the prostate. Identifying them will potentially help us recognize in advance cancers that are likely to spread and develop therapies for them.