High Definition Clonal Analyses of Archival Pancreatic Adenocarcinoma Samples
存档胰腺腺癌样本的高清克隆分析
基本信息
- 批准号:8035406
- 负责人:
- 金额:$ 24.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-03-01 至 2013-02-28
- 项目状态:已结题
- 来源:
- 关键词:Adenocarcinoma CellAdmixtureAneuploid CellsAneuploidyBiocompatible MaterialsBiological AssayBiopsyCell FractionCell LineCellsClinicalClonal EvolutionClonal ExpansionComplexCytokeratinDNADataDetectionDevelopmentDiagnosticDiploid CellsDiploidyFlow CytometryFormalinFreezingGenomeGenomic InstabilityGenomicsGrowthHeterogeneityHumanHuman CharacteristicsIndividualInterventionLeadLesionMalignant NeoplasmsMalignant neoplasm of pancreasMapsMasksMeasuresMethodsMolecularNeoplasmsNormal CellOligonucleotidesOrganOutcomePancreasPancreatic AdenocarcinomaPancreatic carcinomaParaffin EmbeddingPathway interactionsPatientsPatternPloidiesPopulationPreparationProcessProtocols documentationResistanceResolutionResourcesSamplingSiteSorting - Cell MovementSpecimenSystemTechnologyTherapeuticTissuesTumor TissueValidationWorkanticancer researchaurora-A kinasebasecancer genomecancer therapyfollow-uphypoxia inducible factor 1improvedin vivointerestneoplasticneoplastic cellnew therapeutic targetnext generationnovelresearch studytumor
项目摘要
DESCRIPTION (provided by applicant): Genomic instability appears to cooperate with Darwinian selection to promote cancer formation through a process in which genomic aberrations occur at accelerated rates, and those alterations that provide a selective growth advantage lead to clonal evolution and expansion. Consequently the patterns of genomic aberrations in cancers can vary extensively, even in tumors arising in the same organ site. A fundamental hypothesis of current cancer genome efforts is that tumor cells become differentially resistant or sensitive to available clinical interventions according to selected aberrations present in each sample and the pathways that they target. Thus the identification of selected aberrations in patient samples will help develop novel therapeutic targets that can be advanced for improved more personalized approach to the treatment of cancer. Recent advances in genomic technologies provide highly detailed analyses of samples of interest. For example oligonucleotide CGH arrays can distinguish single copy changes across an entire genome at intragenic mapping resolution with probe error rates of <5%. A challenge in studying complex tissues is the presence of admixtures of cells and the polyclonal nature of human neoplasias. Furthermore, in addition to masking critical genomic aberrations, the presence of clonal mixtures of neoplastic cell populations in biopsies makes it prohibitively difficult to discern which genomic aberrations occur concurrently and to comprehensively define the genomic contexts of patient samples. Formalin fixed paraffin embedded (FFPE) tissues are a vast resource of clinically annotated samples with patient follow-up data including diagnostic and therapeutic outcomes. As such, these samples represent highly desirable and informative materials for the application of high definition genomics that could improve patient management and provide the molecular basis for the selection of personalized therapeutics. However a major limitation to the use of these samples for high resolution genomic analyses to date is the highly variable quality of the DNA extracted from samples of interest. Flow cytometry has been used to identify and isolate neoplastic clones from primary biopsies in a variety of tissues using objective quantifiable markers. Once identified individual populations can be flow purified to greater than 95% purity for subsequent molecular analyses. We have recently developed methods that adapt single parameter flow cytometry of fresh frozen samples to high definition clonal aCGH analyses of pancreatic cancer. The overall objective of this application is to extend these methods by developing and validating multiparameter flow cytometry assays that are compatible with high definition array CGH analyses and next generation sequencing of clinical samples. These will include diploid and aneuploid cell populations from formulin fixed paraffin embedded (FFPE) samples of pancreatic adenocarcinomas.
描述(由申请人提供):基因组不稳定性似乎与达尔文选择相配合,通过基因组畸变加速发生的过程促进癌症形成,而那些提供选择性生长优势的改变导致克隆进化和扩增。因此,癌症中基因组畸变的模式可能有很大差异,即使是在同一器官部位产生的肿瘤也是如此。当前癌症基因组工作的一个基本假设是,根据每个样本中存在的选定畸变及其针对的途径,肿瘤细胞对可用的临床干预措施产生不同的抵抗力或敏感性。因此,识别患者样本中选定的畸变将有助于开发新的治疗靶点,这些靶点可以进一步改进,以改进更个性化的癌症治疗方法。基因组技术的最新进展提供了对感兴趣样本的高度详细的分析。例如,寡核苷酸 CGH 阵列可以以基因内作图分辨率区分整个基因组中的单拷贝变化,探针错误率<5%。研究复杂组织的一个挑战是细胞混合物的存在和人类肿瘤的多克隆性质。此外,除了掩盖关键的基因组畸变之外,活检中肿瘤细胞群克隆混合物的存在使得辨别同时发生的基因组畸变和全面定义患者样本的基因组背景变得极其困难。福尔马林固定石蜡包埋 (FFPE) 组织是临床注释样本的巨大资源,其中包含患者随访数据,包括诊断和治疗结果。因此,这些样本代表了高清晰度基因组学应用中非常理想和信息丰富的材料,可以改善患者管理并为选择个性化治疗提供分子基础。然而,迄今为止,使用这些样本进行高分辨率基因组分析的一个主要限制是从感兴趣样本中提取的 DNA 质量差异很大。流式细胞术已用于使用客观的可量化标记从各种组织的原发性活检中识别和分离肿瘤克隆。一旦鉴定出个体群体,就可以将其纯化至 95% 以上的纯度,以用于后续的分子分析。我们最近开发了一种方法,可将新鲜冷冻样品的单参数流式细胞术应用于胰腺癌的高清克隆 aCGH 分析。该应用的总体目标是通过开发和验证与高清阵列 CGH 分析和下一代临床样本测序兼容的多参数流式细胞术测定来扩展这些方法。这些将包括来自胰腺腺癌的配方固定石蜡包埋 (FFPE) 样品的二倍体和非整倍体细胞群。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
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Michael T Barrett其他文献
Michael T Barrett的其他文献
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{{ truncateString('Michael T Barrett', 18)}}的其他基金
Monitoring Immunotherapy Response via Gene Silencing Landscapes in Cell-Free DNA
通过游离 DNA 中的基因沉默景观监测免疫治疗反应
- 批准号:
10760450 - 财政年份:2023
- 资助金额:
$ 24.96万 - 项目类别:
HRD-IA signatures in pancreatic ductal adenocarcinoma
胰腺导管腺癌中的 HRD-IA 特征
- 批准号:
10515859 - 财政年份:2022
- 资助金额:
$ 24.96万 - 项目类别:
HRD-IA signatures in pancreatic ductal adenocarcinoma
胰腺导管腺癌中的 HRD-IA 特征
- 批准号:
10551899 - 财政年份:2022
- 资助金额:
$ 24.96万 - 项目类别:
High Definition Clonal Analyses of Archival Pancreatic Adenocarcinoma Samples
存档胰腺腺癌样本的高清克隆分析
- 批准号:
8220862 - 财政年份:2010
- 资助金额:
$ 24.96万 - 项目类别:
High Definition Clonal Analyses of Archival Pancreatic Adenocarcinoma Samples
存档胰腺腺癌样本的高清克隆分析
- 批准号:
7778986 - 财政年份:2010
- 资助金额:
$ 24.96万 - 项目类别:
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