Correlating Environmental & Genetic Risk Factors with Molecular Signatures in

原发性黑色素瘤可以是致命的，也是不可预测的；细小黑色素瘤的子集可以表现为 侵袭性的，而更高级的黑色素瘤的子集可以表现出懒惰的行为。我们不会 理解，当然也不能预测这种生物行为。分子分析，包括 转录图谱(TP)揭示了其他癌症中意想不到的异质性，提示 管理和结果。最近，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*状态以及胚系MCIR等位基因；然而， 由于技术原因，大多数原发黑色素瘤的转录图谱是不可能的。自2001年以来， 哈佛大学皮肤孢子研究人员对200例黑色素瘤进行了TP检查，其中包括31例罕见的冰冻黑色素瘤 原发黑色素瘤，几种细胞系，以及许多新鲜或冷冻的转移灶和短期培养。 引人注目的是，生物信息学分析揭示了TP签名定义的两种截然不同的黑色素瘤： 一种是MITF及其相关基因的高表达，另一种是MITF及相关基因的高表达 免疫、炎症和生长因子基因(IIG)。所有的黑色素瘤都以极高的信心进行了分离 由TP签名定义的这两个类中的一个。与此同时，孢子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小学验证了这两个签名 黑色素瘤；因此，现在有大量的原发黑色素瘤可用于TP。对于项目5， 哈佛大学皮肤孢子研究人员已经确定并招募了几个独特的队列和服务员 FFPE原发黑色素瘤(统称，n&gt；1300)，包括护士健康研究1和2以及健康 专业人士跟踪研究(环境风险暴露数据)，哈佛家族性黑色素瘤 注册(具有大量遗传数据)，以及评估美司他丁(MLSN)效用的两项结果研究 作为一种预测生物标志物。在项目5中，调查人员将关联初级的MITF/IIG TP签名 黑色素瘤有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)预后和结果指标(MLSN 1和2)。远大研究所、核心B和核心C将促进项目5调查员在 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 以前可用，目标是告知预防、诊断、管理和结果战略 这种致命的人类癌症。

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.