Stanford Molecular and Cellular Characterization Laboratory

斯坦福大学分子和细胞表征实验室

• 批准号: 9145163
• 负责人: JAMES D. BROOKS
• 金额: $ 62.48万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-16 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9145163
• 关键词: Address; Basement membrane; Biological; Biological Markers; Biology; Biopsy; Cancer Patient; Carcinoma; Cell Lineage; Cells; Clinical; Clinical Trials; DNA Sequence Alteration; DNA copy number; Data; Death Rate; Detection; Development; Diagnosis; Drops; Early treatment; Epithelial; Event; Evolution; Financial cost; Formalin; Freezing; Gene Expression; Gene Expression Profiling; Genetic Transcription; Genomics; Gleason Grade for Prostate Cancer; Glycoproteins; Growth; Hereditary Disease; Heterogeneity; Histologic; Histology; Indolent; Intraepithelial Neoplasia; Laboratories; Lesion; Malignant Neoplasms; Malignant neoplasm of prostate; Molecular; Molecular Genetics; Morbidity - disease rate; Nature; Neoplastic Epithelial Cell; Organ; Outcome; Ovary; Paraffin Embedding; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Phylogenetic Analysis; Phylogeny; Physicians; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Protein Glycosylation; Proteins; Proteome; Proteomics; Radical Prostatectomy; Recurrence; Sampling; Sensitivity and Specificity; Serum; Specimen; Staging; Technology; Testing; Tissues; Transcript; Trees; Uncertainty; Work; adverse outcome; base; body system; candidate marker; clinically relevant; clinically significant; cohort; glycoproteomics; improved; killings; men; prognostic; prostate carcinogenesis; protein expression; public health relevance; screening; success; tissue fixing; tool; transcriptome; tumor

 DESCRIPTION (provided by applicant): Recent suggests that in the U.S. prostate cancer is over-detected and over-treated resulting in significant morbidity and financial costs. These problems are the product of poor sensitivity and specificity serum Prostate Specific Antigen (PSA) as a screening tool, leading to many unnecessary biopsies that find small and predominantly indolent prostate tumors. While many prostate cancers should be managed with active surveillance, uncertainties surrounding available clinical tools of aggressiveness (such as PSA, Gleason score and clinical stage) will often drive patients and physicians to treatment. Attempts to improve prognostication using candidate biomarkers, mostly discovered from genomic analyses of large pieces of cancers, have had few successes, and available molecular tools provide only modest prediction at best. Clearly, a better understanding of the early molecular genetic events in prostate cancer is desperately needed. We hypothesize that early prostate cancer arises from definable molecular alterations in precursor lesions and progresses as a result of acquired lesions that confer aggressive features in a subpopulation of cells in precursor lesions and/or early tumors. In addition, we hypothesize that at each step, there are downstream molecular alterations that confer, in a probabilistic sense, the ability for some lesions to grow and spread and in others an indolent phenotype (dead end lesions). As such, defining the earliest genomic events, the evolutionary pathways to invasive carcinoma, the final constellation of genomic alterations, and the extent of genomic heterogeneity (the building blocks for evolution), should illuminate the key genomic features distinguishing good and bad outcome prostate cancer. In depth characterization of early lesions has been constrained by limitations of conventional histology tools (prostate cancer precursors can only be reliably identified in fixed tissues) and of available genomic and proteomic technologies (which do not work well on fixed tissues). To address the challenges we wil take advantage of technologies we have developed to analyze small samples in both fixed and frozen tissue to provide a complete picture of the early events in prostate carcinogenesis. We propose 1) to investigate the early genomic evolution of good and bad outcome prostate cancer in histologically defined prostate cancers and precursor lesions in fixed tissues; and 2) to define the genomic heterogeneity of good and bad outcome prostate cancer and the downstream consequences in transcript, protein and glycoprotein expression in frozen tissues. An integrated approach using fixed and frozen tissues will allow us to delineate the early genomic lesions in prostate cancer, define which are selected to evolve into more aggressive and which end up as non-aggressive (dead end) lesions, and characterize the downstream effects of these selected changes in cellular transcription, protein expression and protein glycosylation. A systematic study of the events in prostate cancer during its development and evolution will help address the issues of over- treatment by providing prognostic features and biomarkers that help select men for definitive treatment or observation.

 描述(由申请人提供)：最近的研究表明，在美国，前列腺癌被过度发现和过度治疗，导致了严重的发病率和经济成本。这些问题是由于血清前列腺特异性抗原(PSA)作为筛查工具的敏感性和特异性较差造成的，导致许多不必要的活检发现了小的且主要是惰性的前列腺癌。虽然许多前列腺癌应该通过积极的监测来管理，但围绕现有临床侵袭性工具(如PSA、Gleason评分和临床分期)的不确定性往往会促使患者和医生进行治疗。使用候选生物标记物改善预测的尝试几乎没有成功，可用的分子工具充其量只能提供适度的预测。候选生物标记物大多是从大片癌症的基因组分析中发现的。显然，迫切需要更好地了解前列腺癌的早期分子遗传学事件。我们假设早期前列腺癌起源于前驱病变中可明确的分子改变，并作为获得性病变的结果，这些病变赋予前驱病变和/或早期肿瘤的细胞亚群侵袭性特征。此外，我们假设，在每一步，都有下游的分子变化，在概率意义上，赋予一些病变生长和扩散的能力，而在另一些病变中，赋予懒惰的表型(死胡同病变)。因此，定义最早的基因组事件、侵袭性癌的进化路径、基因组改变的最终星座以及基因组异质性的程度(进化的基石)，应该阐明区分前列腺癌好的和坏的结果的关键基因组特征。对早期病变的深入描述受到传统组织学工具(前列腺癌前体只能在固定组织中可靠地识别)和现有基因组和蛋白质组技术(在固定组织上不起作用)的限制。为了应对挑战，我们将利用我们开发的技术来分析固定和冷冻组织中的小样本，以提供前列腺癌发生的早期事件的完整图景。我们建议1)在组织学定义的前列腺癌和固定组织中的前驱病变中研究前列腺癌良好和不良结局的早期基因组进化；以及2)确定前列腺癌良好和不良结局的基因组异质性以及冰冻组织中转录、蛋白质和糖蛋白表达的下游后果。使用固定和冷冻组织的综合方法将使我们能够描绘前列腺癌的早期基因组病变，定义哪些被选择演变为更具侵袭性的病变，哪些最终成为非侵袭性(死胡同)病变，并表征这些选定的细胞转录、蛋白质表达和蛋白质糖基化变化的下游影响。对前列腺癌发展和演变过程中的事件进行系统研究，将通过提供有助于选择男性进行明确治疗或观察的预后特征和生物标记物，帮助解决过度治疗的问题。