Identification of Melanoma Brain Metastasis Tumor Biomarkers

描述(申请人提供)：由于黑色素瘤在美国的发病率不断上升，其脑转移的频率很高，黑色素瘤脑转移(MBM)日益成为一个重要的临床问题。在缺乏MBM的预测生物标志物的情况下，MBM的早期识别和有效管理仍然不足以损害国家的医疗经济和患者的生活质量。我们将鉴定作为MBM特征的基因组和表观基因组异常。然后，我们将开发和验证这些分子异常，将其作为III和IV期黑色素瘤的预测分子MBM生物标志物信号(S)，以预测MBM发生的高风险。我们的主要假设是，特定的基因组和表观基因组生物标记物可以被识别为MBM的标志，并用于第三期和早期IV期黑色素瘤的转移以发生MBM。这些特定的目标是基于我们对MBM中确定的基因组和表观基因组畸变的强有力的初步研究。具体目标如下：目标I.确定并开发一组标志性的MBM基因组生物标记物，这些标志物可作为III期和IV期黑色素瘤发生MBM的预测生物标志物。单核苷酸多态(SNP)将用于确定拷贝数变异(CNV)的损失和收益作为预测生物标记物使用定制的定量聚合酶链式反应分析。然后，优先排序的MBM基因组生物标志物将被评估为MBM发生的预测因子。目的II.确定和开发一组标志性的表观基因组MBM生物标志物，这些标志物可作为MBM发生的III期和IV期早期预测生物标志物。甲基化阵列和定量甲基化特异的聚合酶链式反应分析已经被用于筛选和识别MBM的生物标记物特征。这些可预测的MBM表观基因组生物标记物随后将被开发并通过优化的甲基化特异性定量PCR分析进行分析。然后，优先排序的MBM表观基因组生物标志物将被评估为MBM发生的预测因子。目的III.验证基因组和/或表观基因组MBM生物标记物预测III和IV期转移的MBM标志物(S)。在AIMS I和II中确定的最佳MBM生物标记物标记组合将分别在III和IV期转移的患者中进行测试，以了解他们预测MBM发生的能力，使用III期多中心临床试验的患者 已经接受了手术切除以恢复无病状态。这些研究将验证高危III和IV期患者发展为MBM的黑色素瘤亚型，识别新的治疗靶点，并识别MBM分子签名。

DESCRIPTION (provided by applicant): Due to the escalating incidence rate of melanoma in the USA and its high frequency to metastasize to the brain, melanoma brain metastasis (MBM) poses an increasingly significant clinical problem. In the absence of predictive biomarkers for MBM, early recognition and effective management of MBM remain inadequate to the detriment of the nation's healthcare economy and patients' quality of life. We will identify genomic and epigenomic aberrations that are signatures of MBM. We will then develop and verify these molecular aberrations as predictive molecular MBM biomarker signature(s) of stage III and IV melanomas for high-risk of MBM occurrence. Our main hypothesis is that specific genomic and epigenomic biomarkers can be identified as signatures of MBM and utilized for stage III and early stage IV melanoma metastasis for MBM occurrence. The specific Aims are based on our strong preliminary studies on genomic and epigenomic aberrations identified in MBM. The Specific Aims are as follows: Aim I. Identify and develop a signature panel of MBM genomic biomarkers that can be used as predictive biomarkers in stage III and IV melanoma for MBM occurrence. Single-nucleotide polymorphism (SNP) will be used to identify copy number variations (CNV) for losses and gains as predictive biomarkers using customized quantitative PCR assays. Prioritized MBM genomic biomarkers will then be assessed as predictors of MBM occurrence. Aim II. Identify and develop a signature panel of epigenomic MBM biomarkers that can be used as predictive biomarkers in stage III and early stage IV for MBM occurrence. Methylation array and quantitative methylation-specific PCR assays have been used to screen and identify biomarker signatures of MBM. These predictive MBM epigenomic biomarkers will then be developed and analyzed by optimized quantitative methylation-specific PCR assays. Prioritized MBM epigenomic biomarkers will then be assessed as predictors of MBM occurrence. Aim III. Verify a MBM predictive signature(s) of genomic and/or epigenomic MBM biomarkers for stage III and IV metastasis. The optimal MBM biomarker signature panel identified in Aims I and II will be tested in patients with stage III and IV metastases, respectivey, for their ability to predict MBM occurrence using phase III multicenter clinical trial patients who have undergone surgical resection to be rendered disease-free. The studies will verify high-risk stage III and IV patients' melanoma subtypes developing into MBM, identification of new targets for therapy, and identification of MBM molecular signatures.