Genetics of Germline Gene Expression Phenotype in Aggressive Prostate Cancer

侵袭性前列腺癌种系基因表达表型的遗传学

• 批准号: 7446665
• 负责人: Liang Wang
• 金额: $ 18.13万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7446665
• 关键词: Aggressive behavior; Alleles; Behavior; Benign; Biochemical Process; Biological Markers; Cancer Patient; Candidate Disease Gene; Cessation of life; Clinical; Clinical Management; Code; Complex; DNA Sequence; Disease; Functional RNA; Gene Expression; Gene Expression Profile; Gene Frequency; Genes; Genetic; Genetic Determinism; Genetic Markers; Genetic Variation; Genotype; Gleason Grade for Prostate Cancer; Human; Individual; Indolent; Inherited; Link; Local Therapy; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Measures; Methods; Microarray Analysis; Molecular; Molecular Profiling; Nature; Neoplasm Metastasis; Non-Malignant; Organ; Outcome; Patients; Pattern; Phenotype; Play; Preventive screening; Proteins; Range; Research Design; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Role; Seeds; Severities; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Staging; Surveys; Symptoms; Therapeutic Studies; Time; Tissues; Transcript; Variant; base; bone; cancer risk; gene discovery; genetic linkage analysis; genetic risk factor; insight; lymph nodes; novel; trait; tumor

DESCRIPTION (provided by applicant): Prostate cancer ranges in severity from relatively benign to extremely aggressive. Some prostate cancers are slow growing, causing few clinical symptoms. In these cases, a patient will most often die with prostate cancer rather than from prostate cancer. Aggressive cancers spread rapidly to the lymph nodes, other organs and in particular, bone. Death usually results from aggressive behavior of this form of cancer. Therefore, there is a critical need to identify those individuals at high risk for aggressive disease as this could have a significant impact on the clinical management of prostate cancer. Genetics is believed to play an important role in determining prostate cancer risk and outcome of prostate cancer. Conventional methods such as linkage analysis and gene association study have proved less successful in identifying genes responsible for prostate cancer. We believe that gene expression profiles can be a product of genotype, and the aggressiveness signature genes may arise through a heritable trait or traits that may represent a risk factor for developing more severe form of prostate cancer. Therefore, we hypothesize that variation in gene expression strongly influences tumor behavior and clinical outcome of prostate cancer. The levels of gene expression function as surrogates for genetic markers that can map the gene variants which underlie both the gene-expression changes and tumor aggressiveness. There are three specific aims for this study: 1). To identify and validate a set of signature transcripts that are differentially expressed in non-malignant tissues between patients with more aggressive and patients with less aggressive prostate cancer; 2). To map genetic determinants of these signature transcripts. 3). To characterize selected candidate genes and their roles in aggressive prostate cancer. To accomplish these, we will survey all known human genes for their expression in normal non-malignant tissues of prostate cancer patients. We will evaluate the inherited expression difference between patients with more aggressive cancer and patients with less aggressive cancer and identify a set of signature genes that may be used as genetic markers for prediction of aggressive prostate cancer. We will investigate genetic determinants of these signature genes using single nucleotide polymorphisms as genetic markers and gene expression level as quantitative trait. We will also explore the role of these signature genes in aggressive prostate cancer by performing large scale gene association study. The proposed study will help us identify genetic risk factors and markers responsible for aggressive behavior of prostate cancer. More importantly, characterization of inherited gene expression signature could point to targets for screening, preventive and therapeutic studies.

描述（由申请人提供）：前列腺癌的严重程度从相对良性到极具侵袭性。有些前列腺癌生长缓慢，几乎没有临床症状。在这种情况下，患者通常会死于前列腺癌而不是前列腺癌。恶性肿瘤会迅速扩散到淋巴结、其他器官，尤其是骨骼。这种癌症的侵略性行为通常导致死亡。因此，迫切需要识别那些具有侵袭性疾病高风险的个体，因为这可能对前列腺癌的临床管理产生重大影响。遗传学被认为在决定前列腺癌的风险和预后方面起着重要作用。传统的方法，如连锁分析和基因关联研究，在确定前列腺癌的基因方面不太成功。我们认为基因表达谱可能是基因型的产物，攻击性特征基因可能是通过一种或多种遗传特征产生的，这些遗传特征可能代表了发展为更严重形式的前列腺癌的风险因素。因此，我们假设基因表达的变异强烈影响前列腺癌的肿瘤行为和临床结果。基因表达水平作为遗传标记的替代品，可以绘制基因变异，这些变异是基因表达变化和肿瘤侵袭性的基础。本研究有三个具体目的：1)。识别和验证一组签名转录本，这些转录本在侵袭性较强和侵袭性较弱前列腺癌患者的非恶性组织中差异表达；2）. 绘制这些签名转录本的遗传决定因素。3）. 目的：描述选定的候选基因及其在侵袭性前列腺癌中的作用。为了完成这些，我们将调查所有已知的人类基因在前列腺癌患者正常非恶性组织中的表达。我们将评估侵袭性较强的癌症患者和侵袭性较弱的癌症患者之间的遗传表达差异，并确定一组可能用作预测侵袭性前列腺癌遗传标记的特征基因。我们将使用单核苷酸多态性作为遗传标记和基因表达水平作为数量性状来研究这些特征基因的遗传决定因素。我们还将通过大规模的基因关联研究来探讨这些特征基因在侵袭性前列腺癌中的作用。这项研究将帮助我们确定前列腺癌侵袭性行为的遗传风险因素和标志物。更重要的是，遗传基因表达特征的表征可以为筛选、预防和治疗研究提供靶点。