Correlating Environmental & Genetic Risk Factors with Molecular Signatures in

关联环境

• 批准号: 8332867
• 负责人: David John Hunter
• 金额: $ 29.81万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8332867
• 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; Classification; Clinical; Cohort Studies; Collection; Communities; Computational Biology; Counseling; Cutaneous; Cutaneous Melanoma; DNA; Data; Development; Diagnosis; Disease; Disease Outcome; Early treatment; Educational process of instructing; Environmental Exposure; Environmental Risk Factor; Epidemiology; Event; Evolution; Excision; Exhibits; Follow-Up Studies; Formalin; Freezing; Funding; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Generations; Genes; Genetic; Genetic Annotation; Genetic Determinism; Genetic Transcription; 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; Neoplasm Metastasis; 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; Recording of previous events; Recruitment Activity; Registries; Reporting; 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; community setting; computerized data processing; effective therapy; follow-up; genetic analysis; genetic risk factor; genome-wide; indexing; insight; melanocyte; melanoma; new technology; novel; outcome forecast; prognostic; prognostic indicator; 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.

原发性黑色素瘤可能是致命的且不可预测。薄黑色素瘤的一个子集可能表现得非常 攻击性的，而更晚期的黑色素瘤的一部分可以表现出惰性行为。我们不 理解但当然无法预测这种生物行为。分子分析，包括 转录谱（TP）揭示了其他癌症中意想不到的异质性， 管理和结果。最近，人们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* 状态以及种系 MCIR 等位基因；然而， 由于技术原因，大多数原发性黑色素瘤的转录分析是不可能的。自2001年以来， 哈佛皮肤 SPORE 研究人员已对超过 200 种黑色素瘤进行了 TP，其中包括 31 种罕见的冷冻肿瘤 原发性黑色素瘤、几种细胞系以及许多新鲜或冷冻的转移性病变和短期培养物。 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： 一种是 MITF 及相关基因的高表达，另一种是 MITF 和相关基因的高表达。 免疫、炎症和生长因子基因 (IIG)。所有黑色素瘤均已高可信度分离 进入由 TP 签名定义的这两个类之一。与此同时，SPORE 调查人员也帮助翻译 一种称为 DASL 的新型 TP 平台，可以分析福尔马林固定石蜡包埋的组织 （FFPE）。最近的实验使用 DASL 平台验证了 FFPE 初级中的这两个签名 黑色素瘤；因此，现在大量的原发性黑色素瘤可用于 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群体 FFPE 原发性黑色素瘤（总共 n>1300），包括护士健康研究 1 和 2 以及健康 专业人士跟踪研究（包含环境风险暴露数据），哈佛家族性黑色素瘤 登记处（具有大量遗传数据）和两项评估褪黑激素效用的结果研究 (MLSN) 作为预后生物标志物。在项目 5 中，研究人员将关联主要的 MITF/IIG TP 签名 具有 1) 遗传变量的黑色素瘤，包括体细胞 (NRASVBRAF*) 和种系 (MCIR)，2) 风险和 环境暴露变量（NHS1.2 和 HPFS），以及 3）预后和结果测量（MLSN 1&2）。布罗德研究所、核心 B 和核心 C 将促进项目 5 研究人员在 数据的生成、分析和解释。预计在未来五年内，项目 5 将 对临床注释的黑色素瘤提供比以往更高水平的分子遗传学分析 之前可用，目的是为疾病的预防、诊断、管理和结果策略提供信息 这种致命的人类癌症。