Genetic & epigenetic analysis of angiogenesis genes in recurrent prostate cancer

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• 批准号: 8098046
• 负责人: Jong Y. Park
• 金额: $ 46.39万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8098046
• 关键词: 5 year old; Algorithms; Angiogenesis Pathway; Area Under Curve; Bioinformatics; Biological; Biological Markers; Biopsy; Blood Circulation; Body part; Cancer Center; Cancer Etiology; Cancer Patient; Candidate Disease Gene; Caucasians; Caucasoid Race; Classification; Clinical; Clinical Treatment; DNA; DNA Methylation; Data; Decision Making; Diagnosis; Disease; Epidemiologic Studies; Epigenetic Process; Evaluation; Formalin; Gene Silencing; Genes; Genetic; Genetic Variation; Genotype; Gleason Grade for Prostate Cancer; Goals; Haplotypes; Hazard Models; Health; Individual; Inherited; Intervention; Length; Linkage Disequilibrium; Logistic Regressions; Lymphatic System; Machine Learning; Malignant neoplasm of prostate; Medical Records; Methylation; Modality; Modeling; Molecular; Morbidity - disease rate; Mutation; Neoplasm Metastasis; Nomograms; Operative Surgical Procedures; Outcome; Paraffin Embedding; Pathology; Pathway interactions; Patient observation; Patients; Phase; Play; Promoter Regions; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; RNA; Race; Radical Prostatectomy; Receiver Operating Characteristics; Recurrence; Regulation; Research; Research Institute; Risk; Role; Serum; Source; Staging; TNM; Techniques; Testing; Time; Tissues; Trees; Tumor Tissue; United States; Variant; abstracting; angiogenesis; base; bone; cancer recurrence; cancer site; cancer therapy; case control; cohort; design; follow-up; genetic profiling; genetic variant; improved; men; mortality; neoplasm registry; outcome forecast; tumor

DESCRIPTION (provided by applicant): Prostate is the most common site of cancer in men in the United States. Most prostate cancers progress relatively slowly and stay confined within the prostate. However, some cases grow aggressively and metastasize to other parts of the body. The most important clinical challenge in the treatment of the disease is the not knowing which of these two clinical forms a patient is presenting with. This is critically important information given the significant morbidity associated with treatment interventions and could eventually help distinguish men who need intensive treatment from those who may be better served by watchful waiting. Currently, the level of serum PSA, clinical stage and Gleason score are used to estimate prognosis and inform treatment modalities. Although they are very useful, additional biomarkers may help to better predict the outcome of prostate cancer. Carefully designed molecular epidemiologic studies can contribute in this arena. Although the significance of angiogenesis in prostate cancer is demonstrated by its correlation with clinical features, such as clinical stage, Gleason scores, progression, metastasis and survival, relatively few studies have assessed the role of genes involved in the angiogenesis pathway with recurrence of prostate cancer. Research to identify the specific genes and genetic variants relevant to angiogenesis risk remain largely unexplored. Part of the reason why candidate gene studies have been inconclusive may be that a major source of genetic regulation has been ignored: gene silencing through DNA methylation. Our hypothesis is that genetic and epigenetic individual variation in genes involved in the angiogenesis pathway is associated with recurrence of prostate cancer. The ultimate goal of this study is to identify biomarkers that can be used at the time of diagnosis to predict prognosis and improve clinical treatment decision making. The proposed study involves (1) construction of a historical cohort of prostate cancer cases (n=~1300) treated with radical prostatectomy at the H. Lee Moffitt Cancer Center between 1987 and 2003, (2) evaluating the association between 802 SNPs in 52 genes involved in angiogenesis with risk of recurrent prostate cancer, (3) evaluating the association between DNA methylation in the promoter regions of angiogenesis genes and risk for recurrence of prostate cancer and (4) testing the combined effects of inherited and acquired genetic changes in the candidate genes on disease aggressiveness. PUBLIC HEALTH RELEVANCE: These studies will provide key information regarding the potential effect of epigenetic genetic variations on prostate cancer recurrence. The combination of the individual's epigenetic and genetic profile and a current prediction model can possibly estimate a more accurate recurrence risk of the prostate cancer patients. This model can be extremely useful for a strategy of prostate cancer treatment.

描述（由申请人提供）：前列腺是美国男性最常见的癌症部位。大多数前列腺癌进展相对缓慢并且局限于前列腺内。然而，有些病例会急剧生长并转移到身体的其他部位。该疾病治疗中最重要的临床挑战是​​不知道患者出现的是这两种临床形式中的哪一种。考虑到与治疗干预相关的显着发病率，这是至关重要的信息，并最终有助于区分需要强化治疗的男性和那些通过观察等待可能得到更好服务的男性。目前，血清 PSA 水平、临床分期和格里森评分用于估计预后并为治疗方式提供信息。尽管它们非常有用，但其他生物标志物可能有助于更好地预测前列腺癌的结果。精心设计的分子流行病学研究可以在这一领域做出贡献。尽管血管生成在前列腺癌中的重要性是通过其与临床特征（例如临床分期、格里森评分、进展、转移和生存）的相关性来证明的，但相对较少的研究评估了参与血管生成途径的基因与前列腺癌复发的作用。识别与血管生成风险相关的特定基因和遗传变异的研究在很大程度上尚未探索。候选基因研究尚无定论的部分原因可能是基因调控的一个主要来源被忽视了：通过DNA甲基化实现基因沉默。我们的假设是，参与血管生成途径的基因的遗传和表观遗传个体变异与前列腺癌的复发相关。这项研究的最终目标是确定可在诊断时用于预测预后和改善临床治疗决策的生物标志物。拟议的研究涉及 (1) 构建 1987 年至 2003 年间在 H. Lee Moffitt 癌症中心接受根治性前列腺切除术治疗的前列腺癌病例历史队列 (n=~1300)，(2) 评估 52 个病例中 802 个 SNP 之间的关联参与血管生成的基因与前列腺癌复发的风险，(3) 评估血管生成基因启动子区域 DNA 甲基化与前列腺癌复发风险之间的关联，以及 (4) 测试候选基因中遗传性和后天性遗传变化对疾病侵袭性的综合影响。公共健康相关性：这些研究将提供有关表观遗传变异对前列腺癌复发的潜在影响的关键信息。个体的表观遗传和遗传图谱与当前的预测模型的结合可能可以更准确地估计前列腺癌患者的复发风险。该模型对于前列腺癌的治疗策略非常有用。