Correlating Environmental & Genetic Risk Factors with Molecular Signatures in

关联环境

• 批准号: 7464272
• 负责人: David John Hunter
• 金额: $ 24.38万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7464272
• 关键词: Address; Adjuvant; Adjuvant Therapy; Algorithms; Alleles; Archives; Awareness; BRAF gene; Behavior; Behavioral; Bioinformatics; Biological; Biological Markers; Biometry; Breslow Thickness; CDKN2A gene; Cell Line; Characteristics; Class; Classification; Clinical; Collection; Communities; Computational Biology; Counseling; Cutaneous; Cutaneous Melanoma; DNA; Data; Depth; Development; Diagnosis; Disease; Disease Outcome; Early Intervention; Educational process of instructing; Environmental Exposure; Environmental Risk Factor; Event; Evolution; Excision; Exhibits; Follow-Up Studies; Formalin; Freezing; Funding; Gene Expression; Gene Expression Profiling; Generations; Genes; Genetic; Genetic Annotation; Genetic Determinism; Genetic Transcription; Genome; Genomics; Goals; Growth; Growth Factor Gene; Health Professional; Hereditary Melanoma; Heterogeneity; Histologic; Human; Human Genome Project; Immune; Individual; Indolent; Inflammation; Inflammatory; Institutes; K-Series Research Career Programs; Ligation; Malignant Neoplasms; Measurement; Measures; Mediating; Melanocytic Neoplasm; Melanoma Cell; Messenger RNA; Metastatic Lesion; Metastatic Melanoma; Methods; Microphthalmos; Molecular; Molecular Analysis; Molecular Genetics; Molecular Profiling; N-ras Genes; NRAS gene; Neoplasm Metastasis; Numbers; Nurses' Health Study; Outcome; Outcome Measure; Outcome Study; Paraffin; Paraffin Embedding; Patients; Pattern; Phenotype; Physiology; Population Sciences; Population Study; Positioning Attribute; Precipitating Factors; Predisposition; Prevention; Purpose; Recording of previous events; Recruitment Activity; Registries; Reporting; Reproduction spores; Research; Research Personnel; Resources; Risk; Risk Factors; Sentinel Lymph Node; Skin; Skin Cancer; Specimen; Structure; Subgroup; Survival Rate; Technology; Therapeutic; Thick; Time; Tissues; Translating; United States; Validation; Variant; base; cancer genomics; cohort; computerized data processing; genetic analysis; genetic risk factor; indexing; insight; melanocyte; melanoma; new technology; novel; outcome forecast; p21 N-Ras Protein; prognostic; research study; response; trend; tumor

Primary melanomas can be both deadly and unpredictable; a subset of thin melanomas can behave very aggressively while a subset of more advanced melanomas can show indolent behavior. We do not understand, and certainly cannot predict, this biological behavior. Molecular analysis, including transcriptional profiling (TP), has revealed unexpected heterogeneity in other cancers, informing management and outcome. Recently, a degree of molecular heterogeneity has been discovered in cutaneous melanoma, including tumor BRAF* and NRAS* status and germline MCIR alleles; however, transcriptional profiling of most primary melanomas has been impossible for technical reasons. Since 2001, Harvard Skin SPORE investigators have performed TP on > 200 melanomas, including 31 rare frozen primary melanomas, several cell lines, and many fresh or frozen metastatic lesions and short term cultures. Strikingly, bio-informatic analysis has revealed two distinct classes of melanoma defined by TP signatures: one characterized by higher expression of MITF and related genes, and the other by higher expression of immune, inflammatory, and growth factor genes (IIG). All melanomas have segregated with high confidence into one of these two classes define by TP signature. In parallel, SPORE investigators have helped translate a novel platform forTP, termed DASL, that permits analysis of formalin-fixed paraffin-embedded tissue (FFPE). Using the DASL platform, recent experiments have validated these two signatures in FFPE primary melanomas; accordingly, large numbers of primary melanomas are now available for TP. For Project 5, Harvard Skin SPORE investigators have identified and recruited several unique cohorts with attendant FFPE primary melanomas (collectively, n>1300), including Nurses Health Study 1&2 and Health Professionals Follow up study (with environmental risk exposure data), the Harvard Familial Melanoma Registry (with substantial genetic data), and two outcome studies assessing the utility of melastatin (MLSN) as a prognostic biomarker. In Project 5, investigators will correlate the MITF/IIG TP signatures of primary melanomas with 1) genetic variables, including somatic (NRASVBRAF*) and germline (MCIR), 2) risk and environmental exposure variables (NHS1.2 and HPFS), and 3) prognosis and outcome measures (MLSN 1&2). The Broad Institute, Core B, and Core C will facilitate the activities of Project 5 investigators in the generation, analysis and interpretation of the data. Over the next five years, it is expected that Project 5 will deliver a higher level of molecular genetic analysis of clinically annotated melanomas than has ever been available before, with the goal of informing prevention, diagnosis, management, and outcome strategies in this deadly human cancer.

原发性黑色素瘤可以是致命的和不可预测的;薄黑色素瘤的一个子集可以表现得非常 而更晚期的黑色素瘤的子集可以表现出惰性行为。我们不 理解，当然也无法预测这种生物行为。分子分析，包括 转录谱分析（TP）揭示了其他癌症中意想不到的异质性， 管理和成果。最近，已经发现了一定程度的分子异质性， 皮肤黑色素瘤，包括肿瘤BRAF* 和NRAS* 状态和生殖系MCIR等位基因;然而， 由于技术原因，大多数原发性黑素瘤的转录谱分析是不可能的。自2001年以来， 哈佛皮肤孢子研究人员已经对200多个黑色素瘤进行了TP，其中包括31个罕见的冷冻肿瘤。 原发性黑色素瘤、几种细胞系和许多新鲜或冷冻的转移病灶和短期培养物。 引人注目的是，生物信息学分析揭示了由TP特征定义的两种不同类型的黑色素瘤： 一种以MITF和相关基因的高表达为特征，另一种以MITF和相关基因的高表达为特征。 免疫、炎症和生长因子基因（IIG）。所有的黑色素瘤都有很高的可信度 这两个类由TP签名定义。与此同时，SPORE的调查人员帮助翻译了 一种新的TP平台，称为DASL，允许分析福尔马林固定的石蜡包埋组织 （FFPE）。使用DASL平台，最近的实验已经在FFPE小学中验证了这两个签名 黑色素瘤;因此，大量的原发性黑色素瘤现在可用于TP。对于项目5， 哈佛皮肤孢子研究人员已经确定并招募了几个独特的队列， FFPE原发性黑色素瘤（共n>1300例），包括护士健康研究1和2以及健康 哈佛家族性黑色素瘤的随访研究（环境风险暴露数据） 登记研究（具有大量遗传数据）和两项评估melastatin（MLSN）效用的结局研究 作为一种预后生物标志物。在项目5中，研究者将主要研究对象的MITF/IIG TP签名 黑色素瘤与1）遗传变量，包括体细胞（NRASVBRAF*）和生殖系（MCIR），2）风险和 环境暴露变量（NHS1.2和HPFS），以及3）预后和结局指标（MLSN 1和2）。Broad Institute、Core B和Core C将促进项目5调查人员在 数据的生成、分析和解释。在未来五年，预计项目5将 提供比以往更高水平的临床注释黑色素瘤的分子遗传学分析 提供之前，与通知的预防，诊断，管理和结果战略的目标， 这种致命的人类癌症