Imaging Guided Genomics of Malignant Transformation

恶性转化的影像引导基因组学

基本信息

批准号：
8649030
负责人：
Joseph F Costello
金额：
$ 60.68万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-08 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8649030
关键词：
3-Dimensional Biological Assay Biology Biopsy Blood Vessels Blood Volume Brain Neoplasms Cell Cycle Cerebrum Characteristics Choline DNA Damage Data Diffusion Evolution Excision Exons Experimental Neoplasms Frequencies Functional Imaging Gene Expression Profile Genetic Genomics Glioblastoma Glioma Goals Grant Human Hypoxia Image Individual Induced Mutation Knowledge Light Link Malignant - descriptor Malignant Neoplasms Measures Metabolic Molecular Cytogenetics Molecular Profiling Mutation Mutation Analysis Mutation Detection Operative Surgical Procedures Outcome Patients Pattern Physiological Probability Property RNA Sequences Recurrence Recurrent disease Relative (related person)Sampling Signal Pathway Testing Time Tissue Sample Tissues Tumor Tissue Validation chemotherapeutic agent chemotherapy disease natural history exome exome sequencing genetic evolution imaging modality in vivo indexing innovation next generation sequencing non-invasive imaging novel public health relevance temozolomide tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): This project will use novel quantitative imaging methods to guide biopsies to biologically distinct regions of brain tumors for targeted exome and transcriptome analysis. Our goal is to identify naturally evolving and treatment-induced mutations that drive malignant transformation (MT) of low grade glioma (LGG) to high grade glioma (HGG). MT is associated with very poor survival, but the mechanisms underlying MT are unknown, and it is not known how chemotherapy following resection of LGG might alter the natural course of tumor evolution. Our substantial preliminary data from exome and RNA sequencing (RNA-seq) suggests that evolution of mutations can differ dramatically in temozolomide (TMZ) treated and non-treated patients, and that this commonly used chemotherapeutic agent itself may induce recurring transformation-promoting driver mutations that converge on common signaling pathways. In contrast to traditional genomic studies, imaging guided genomics could enrich the detection of mutations that drive MT by linking mutations to regions of aggressive tumor growth in vivo. Here we propose to interrogate the genetic underpinnings of MT in TMZ-treated and untreated patients with two complementary approaches. In aim 1, we will use exome and RNA-seq to compare exon mutations and expression profiles among four tumor biopsies from each patient, two with and two without characteristics of MT as predicted by novel physiologic/metabolic imaging parameters and subsequently confirmed by tissue analyses. This will provide a focused assessment of MT from a single surgical time point. In aim 2, we will use longitudinally collected samples from the same individual before and after transition from LGG to HGG. We will compare the mutation and expression profiles within this second set of subjects who have (i) LGG tissue available retrospectively and (ii) image guided tissue samples that were obtained as part of this grant and that demonstrate transformation to HGG. These paired samples will allow a direct assessment of evolution of mutations in individual patients over time. The integration of genomics with advanced imaging, validation of mutation frequency in large, independent set of tumors, experimental assays of candidates, and up-to-date computational analyses are expected to enrich for the identification of mutations that drive MT and to distinguish naturally evolving from TMZ-induced mutations. These studies could therefore impact patient management by identifying LGG patients for which chemotherapy should be contraindicated, and by identifying common and targetable mutations associated with MT.

描述（由申请人提供）：该项目将使用新颖的定量成像方法来指导活检到靶向外观和转录组分析的生物学上不同区域的生物学区域。我们的目标是鉴定自然发展和治疗诱导的突变，这些突变驱动了低级神经胶质瘤（LGG）到高级神经胶质瘤（HGG）的恶性转化（MT）。 MT与非常差的生存有关，但是MT的基础机制尚不清楚，而切除LGG后的化学疗法尚不清楚如何改变肿瘤进化的自然过程。我们来自外来和RNA测序（RNA-SEQ）的大量初步数据表明，突变的演变可能在经过治疗和未经治疗的患者的替莫唑胺（TMZ）中可能发生巨大差异，并且这种常用的化学治疗剂本身可能会诱导转化转化的驱动因素在常见的信号通道上融合。与传统的基因组研究相反，成像引导的基因组学可以丰富通过将突变与体内侵袭性肿瘤生长区域联系起来的突变的检测。在这里，我们建议通过两种互补方法询问MT在TMZ处理和未经治疗的患者中的遗传基础。在AIM 1中，我们将使用外显子和RNA-Seq比较来自每个患者的四个肿瘤活检中的外显子突变和表达谱，两个，两种，两个，没有MT的特征，如新颖的生理/代谢成像参数所预测的，随后通过组织分析证实。这将从单个手术时间点提供对MT的重点评估。在AIM 2中，我们将在从LGG到HGG过渡之前和之后使用纵向收集的样本。我们将在第二组受试者中比较（i）回顾性可用的LGG组织以及（ii）作为该赠款的一部分获得的图像引导的组织样品的突变和表达曲线，并证明了对HGG的转化。这些配对样品将允许随着时间的推移直接评估个别患者突变的演变。基因组学与高级成像的整合，大型独立肿瘤集中突变频率的验证，候选者的实验测定以及最新的计算分析有望丰富，以鉴定驱动MT的突变并与自然发展的突变鉴定 TMZ诱导的突变。因此，这些研究可以通过确定应禁忌化疗的LGG患者，并通过鉴定与MT相关的常见和可靶向突变来影响患者的管理。