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

概述：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独立的研究者，研究前列腺癌的体细胞遗传学，同时保持肿瘤的小型临床实践。我是丹娜-法伯癌症研究所的肿瘤学讲师，在马修·迈耶森博士的实验室接受培训，并获得哈佛大学和麻省理工学院布罗德研究所的额外资源。除了课程学习、出席会议以及Meyerson博士和其他人的指导外，我还提出了一个研究项目，以表征前列腺癌的染色体畸变，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。前列腺癌的特点是其临床异质性，一些癌症仍然是惰性的，而另一些则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。了解这一点可能有助于开发区分侵袭性前列腺癌和惰性前列腺癌的标志物，以及针对导致进行性疾病的分子改变的治疗方法。我们已经开发了一种技术来表征前列腺癌的染色体畸变，包括杂合性缺失（LOH）和拷贝数变化，在高分辨率和整个基因组中，使用单核苷酸多态性（SNP）阵列。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，并为其他靶向区域提供小而有趣的候选基因列表。在这里，我们建议使用该技术来解决前列腺癌进展的体细胞遗传学并验证这些基因靶点，有三个具体目的：1，鉴定染色体畸变，包括LOH和拷贝数改变，在局限性和转移性前列腺癌之间的患病率差异；2、确定候选癌基因和肿瘤抑制基因中的点突变和插入/删除事件，这些突变似乎是这些畸变的目标；3、功能性验证目标1和目标2中选定的候选癌基因。相关性：前列腺癌的发生是由于细胞DNA突变的积累。我们的目标是确定与前列腺癌生长和扩散有关的突变。识别它们将有可能帮助我们提前识别可能扩散的癌症，并为它们开发治疗方法。

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.