Towards Understanding Prostate Cancer Heterogeneity

理解前列腺癌的异质性

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：前列腺癌（PCA）是一种常见的临床异质性疾病，其进展具有显着的变异性。该提案的重点是描述我们小组发现的 PCA 中的一种新易位，并检查该易位在疾病进展中的作用。通过应用新的生物信息学方法，我们的小组发现了 PCA 中的常见易位，涉及雄激素严格调控的基因 TMPRSS2 (21q22.3) 和 ETS 转录因子家族成员 ERG (21q22.2) 或 ETV1 (7p21.2)。这种易位可在侵袭性 PCA 和 20% 的高级前列腺上皮内瘤变 (PIN) 中检测到。 TMPSS2-ERG PCA 与较高的肿瘤分期和 PCA 特异性死亡相关。 TMPRSS2 是雄激素调节程度最高的基因之一。自我们最初的报告以来，我们进一步发现，大约 60% 的 TMPRSS2-ETS 易位肿瘤在 21 号染色体上存在缺失，涉及 TMPRSS2 和 ERG 之间的区域。 CML 中所见的易位相关缺失的存在可能为了解 PCA 的临床和遗传异质性提供重要的见解。因此，我们的总体假设是 TMPRSS2-ETS 家族癌基因融合蛋白驱动 PCA 分子多样性和临床进展。我们建议通过追求以下具体目标来检验这一假设：在目标 1 中，我们将描述 PCA 中与 TMPRSS2-ETS 易位相关的缺失的频率和程度。在目标 2 中，我们将鉴定与不同 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 特异性死亡或转移性疾病发展的预测因子。在本提案结束时，我们将描述各种 PCA 样本 (n>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 检测来对 PCA 进行细分并识别与易位/缺失状态相关的二级分子改变。最后，我们将确定 FISH 检测（或其他原位检测）是否可以用作预后生物标志物。