Towards Understanding Prostate Cancer Heterogeneity

理解前列腺癌的异质性

• 批准号: 7653646
• 负责人: MARK A. RUBIN
• 金额: $ 36.54万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7653646
• 关键词: 17q21; 21q22.2; 21q22.3; 7p21.2; Accounting; Address; Affect; Age; Androgens; Bioinformatics; Biological Assay; Biological Markers; Biology; Cancer Prognosis; Case Study; Cessation of life; Chimeric Proteins; Chromosomal Rearrangement; Chromosome Mapping; Chromosome abnormality; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 9; Chronic Myeloid Leukemia; Clinical; Clinical Pathology; Cloning; Cohort Studies; Computer Analysis; Cytogenetics; Data; Data Set; Development; Diagnosis; Diagnostic; Diagnostic Neoplasm Staging; Disease; Disease Progression; ERG gene; ETV1 gene; ETV4 gene; Epidemiology; Equilibrium; Event; Family; Family member; Fluorescent in Situ Hybridization; Frequencies; Fusion Oncogene Proteins; Gene Amplification; Gene Fusion; Genes; Genetic; Genetic Heterogeneity; Genetic Variation; Genome; Genome Stability; Genomics; Genotype; Health; Hematologic Neoplasms; Heterogeneity; Human; Immunohistochemistry; In Situ; Knowledge; Laboratories; Lead; Lesion; Leukocytes; Ligation; Loss of Heterozygosity; Malignant - descriptor; Malignant neoplasm of prostate; Maps; Molecular; Molecular Biology; Oncogene ETS; Oncogenes; Oncogenic; Outcome; Pathology; Pathway interactions; Patient observation; Physicians; Plasma; Proportional Hazards Models; Prostatic Intraepithelial Neoplasias; Protein Isoforms; Protein Tyrosine Kinase; Published Comment; Publishing; Reporting; Research Personnel; Resolution; Review Committee; Role; Sampling; Single Nucleotide Polymorphism; Solid Neoplasm; Source; Staging; Survival Analysis; TMPRSS2 gene; Techniques; Testing; Time; Tissues; Transcript; Tumor Suppressor Genes; Tumor stage; Validation; Work; base; bcr-abl Fusion Proteins; cohort; density; effusion; follow-up; genome-wide; insight; men; multidisciplinary; novel; population based; prognostic; transcription factor; tumor; tumor progression

DESCRIPTION (provided by applicant): Prostate cancer (PCA) is a common and clinically heterogeneous disease with marked variability in progression. This proposal focuses on characterizing a novel translocation in PCA identified by our group, and examining the role of the translocation in disease progression. By applying a new bioinformatics approach, our group identified a common translocation in PCA, involving the tightly androgen regulated gene TMPRSS2 (21q22.3) and ETS transcription factor family members, either ERG (21q22.2) or ETV1 (7p21.2). This translocation is detected in invasive PCA and in 20% of high-grade prostatic intraepithelial neoplasia (PIN). TMPSS2-ERG PCA are associated with higher tumor stage and PCA specific death. TMPRSS2 is one of the most highly androgen regulated genes. Since our original report, we have further discovered that approximately 60% of tumors with TMPRSS2-ETS translocations harbor deletions on chromosome 21 involving the region between TMPRSS2 and ERG. The presence of translocation-associated deletions, as seen in CML, may provide important insight into the clinical and genetic heterogeneity of PCA. Therefore, our overarching hypothesis is that the TMPRSS2-ETS family oncogene fusion proteins drive PCA molecular diversity and clinical progression. We propose testing this hypothesis by pursuing the following specific aims: In Aim 1, we will characterize the frequency and extent of deletions associated with the TMPRSS2-ETS translocations in PCA. In Aim 2, we will identify critical genomic alterations associated with the distinct TMPRSS2-ETS family translocations and deletions. In Aim 3, we will develop in situ tests to evaluate fusion status as a predictor of PCA specific death or development of metastatic disease. At the conclusion of this proposal, we will have characterized the frequency of TMPRSS2-ETS translocations and deletions in a wide range of PCA samples (n>150) and a population-based cohort (n=1275). We will develop optimized FISH assays to sub-classify PCAs and identify secondary molecular alterations associated with the translocation/deletion status. Finally, we will determine if FISH assays (or other in situ tests) can be employed as a prognostic biomarker.

描述(申请人提供)：前列腺癌(PCa)是一种常见的临床异质性疾病，进展有明显的变异性。这项建议集中于描述我们小组发现的一种新的前列腺癌易位，并研究该易位在疾病进展中的作用。通过应用一种新的生物信息学方法，我们的研究小组发现了一种常见的前列腺癌易位，涉及雄激素严格调控基因TMPRSS2(21q22.3)和ETS转录因子家族成员ERG(21q22.2)或ETV1(7p21.2)。这种易位在侵袭性前列腺癌和20%的高级别前列腺上皮内瘤变(PIN)中被检测到。TMPSS2-ERG-Pca与较高的肿瘤分期和Pca特异性死亡相关。TMPRSS2是雄激素调节最强的基因之一。自从我们最初的报告以来，我们进一步发现，大约60%的TMPRSS2-ETS易位的肿瘤在21号染色体上存在缺失，涉及TMPRSS2和ERG之间的区域。易位相关缺失的存在，如在CML中所见，可能为了解PCa的临床和遗传异质性提供重要的洞察力。因此，我们的主要假设是TMPRSS2-ETS家族癌基因融合蛋白推动了PCa分子多样性和临床进展。我们建议通过追求以下特定目标来验证这一假设：在目标1中，我们将表征与Pca中TMPRSS2-ETS易位相关的缺失的频率和程度。在目标2中，我们将确定与不同的TMPRSS2-ETS家族易位和缺失相关的关键基因组改变。在目标3中，我们将开发原位测试来评估融合状态作为PCa特异性死亡或转移疾病发展的预测因子。在这项建议的结论中，我们将描述广泛的前列腺癌样本(n&gt；150)和基于人群的队列(n=1275)中TMPRSS2-ETS易位和缺失的频率。我们将开发优化的FISH分析方法来对PCA进行细分，并确定与易位/缺失状态相关的二级分子变化。最后，我们将确定FISH分析(或其他原位测试)是否可以用作预后生物标记物。