Characterization of Cancer Transcriptomes using Next Generation Sequencing

描述（由申请人提供）：高通量基因组技术对个性化医疗和新型癌症治疗的影响最终将取决于相应数据的解释能力。因此，申请人的长期目标是通过对高通量基因组技术的综合分析，将基于基因组的知识转化为开发新的癌症诊断、预后和治疗策略。作为这一努力的第一步，本建议关注于常见癌症驱动由非特异性畸变隐藏的复发性基因融合突变的中心假设。我们相信下一代癌症转录组测序可以阐明这些驱动基因融合，因此建立了以下具体目标来实现这一目标：(1)利用基因组学数据的综合分析来检测ETS阴性前列腺肿瘤中新的基因融合；(2)进一步发展生物信息学方法，优先考虑偶发嵌合体，并将这些方法应用于黑色素瘤和胰腺癌；(3)实施基于测序的基因和外显子水平表达异常值分析，以评估患病率，并在公开的数据收集中提名新的基因融合。总的来说，如果这一应用的目标得以实现，我们可能会发现癌症中新的致病靶点，这些靶点可以转化为靶向治疗的发展。即使是成功地发现一个靶点，无论是直接从提议的工作中发现的，还是由另一个实验室利用这项提议所开发的方法发现的，都将对我们如何治疗癌症产生重大影响。

DESCRIPTION (provided by applicant): The impact of high-throughput genomics technologies on personalized medicine and novel cancer treatments will ultimately be determined by the ability to interpret the data accordingly. Therefore, the applicant's long-term objective is to translate genome-based knowledge, through integrative analysis of high- throughput genomic technologies, into the development of novel diagnostic, prognostic, and therapeutic strategies in cancer. As an initial step towards this endeavor, this proposal focuses on the central hypothesis that common carcinomas harbor driving recurrent gene fusion mutations that are hidden by non-specific aberrations. We believe that Next Generation Sequencing of cancer transcriptomes may elucidate these driving gene fusions and therefore established the following specific aims to accomplish this: (1) employ integrative analysis of genomics data to detect novel gene fusions in ETS negative prostate tumors, (2) further develop the bioinformatic approaches to prioritize casual chimeras and apply these methods in melanoma and pancreatic cancer, and (3) implement a sequencing based gene- and exon-level expression outlier profile analysis to assess the prevalence, and nominate novel, gene fusions in publicly available data collections. Overall, if the aims of this application are achieved we may reveal novel pathogenomic targets in cancer that can be translated into the development of a targeted therapy. Even the successful discovery of a single target, whether discovered directly from the proposed work or uncovered by another lab leveraging the methodologies developed as a result of this proposal, will have significant impact on how we treat cancer. The Michigan Center for Translational Pathology has in-depth experience using bioinformatics and genomics for studying gene expression, particularly gene fusions, yielding numerous biomarkers and therapeutic targets in prostate cancer and therefore serves as an ideal environment for supporting the applicant. This can be exemplified by the applicant's extensive preliminary data, which has led to multiple high impact first author manuscripts. Given Dr. Chinnaiyan's excellent record of mentoring biostatisticians and bioinformaticians as they transition into successful independent investigators, he will provide a similar career development plan for the current applicant. The first specific aim, to be completed during the Mentored phase, will focus on detecting gene fusions in prostate cancer and therefore offer critical integrative analysis, cancer biology, and translational research training. The focus of the independent phase will be placed on sequence analysis of chimera detection in newly established cancer transcriptome projects and RNA-Seq based outlier expression analysis to reveal novel therapeutic targets, which will have minimal overlap with, but complements, the mentor's research on prostate gene fusions. Overall, an NIH Pathway to Independence Award will be indispensable for the applicant to become an independent investigator in the much needed field of integrative cancer biology to continue translating genome-based discovering into widely adopting clinical applications. PUBLIC HEALTH RELEVANCE: Characterization of key genetic aberrations in cancers holds the key to the development of early diagnostic markers and effective therapeutic targets. Therefore this proposal seeks funding to detecting novel, recurrent gene fusions using Next Generation transcriptome sequencing of human tumors. Due to their cancer-specific expression, novel gene fusions serve as ideal therapeutic targets that could have a significant impact on how we classify and treat cancer which will ultimately lead to improved patient care.