Biomarker Discovery for the Classification of Melanoma

用于黑色素瘤分类的生物标志物发现

• 批准号: 8146027
• 负责人: Boris C. Bastian
• 金额: $ 8.51万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 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 2011-08-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8146027
• 关键词: Address; Algorithms; American Joint Committee on Cancer; Anatomic Sites; Area; BRAF gene; Behavior; Biological; Biological Markers; Candidate Disease Gene; Categories; Characteristics; Classification; Clinic; Clinical; Clinical Course of Disease; DNA copy number; Data; Data Set; Diagnosis; Differential Diagnosis; Disease; Disease Outcome; Disease-Free Survival; Epidemiology; GNAQ gene; Genes; Genetic; Genetic Markers; Genotype; Germ Lines; Goals; Health; Incidence; Lead; Marker Discovery; Measures; Microscopic; Morphology; Mutation; Neoplasm Metastasis; Outcome; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Predisposition; Prevention therapy; Primary Neoplasm; Process; Publications; Reagent; Recurrence; Role; Sampling; Signal Pathway; Skin Cancer; Stratification; Subgroup; Sun Exposure; Surrogate Markers; Therapeutic Intervention; Tissue Microarray; Training; Ultraviolet Rays; Validation; Variant; Work; base; clinically relevant; clinically significant; cohort; follow-up; improved; indexing; insight; melanoma; mortality; population based; prognostic; public health relevance; response; tumor; tumor registry

DESCRIPTION (provided by applicant): Melanoma is an aggressive form of skin cancer whose overall incidence and mortality rates are increasing worldwide. There is significant unresolved complexity in the clinical and histopathological presentation, relationship to UV light, and epidemiology of melanoma. Attempts to stratify tumors into "histogenetic" types based on the microscopic pattern of the disease have not been broadly accepted in the clinic because of significant overlap between the criteria that are proposed and limited relationship between the classification and clinical course of the disease. Over the past decade our studies of primary melanomas have resulted in the demonstration of genetically distinct subtypes of melanoma that are related to patient germline genotypes, anatomic site of presentation, and to solar exposure. This work has resolved the issue of whether there are meaningful distinctions to be made among melanomas, and moved the field to address the discovery of those differences. Additional progress in this area is critical since current therapies have proven ineffective, perhaps in part because responses in subsets of patients are not recognized. The goal of this proposal is to establish a framework of genetic and phenotypic markers that define disease categories with common mechanistic alterations and to provide markers that can be used for classification, diagnosis, and to identify groups of patients that are likely to respond to emerging therapies targeted against genetic alterations. To achieve this goal we will assemble a phenotypically diverse cohort of 350 primary melanomas by sampling from categories of the existing WHO classification. This discovery and training cohort will used to identify new genetic markers, refine phenotypic assessments and establish classification algorithms based on the genetic, clinical and histopathological characteristics. The provisional classification algorithms will be validated for their ability to produce genetically homogeneous subgroups using an independent cohort of primary tumors, and the association of these subgroups with disease outcome will be determined using a third cohort. Finally we will define surrogate markers using only commonly collected clinical information, and apply them to the 50,000 cases in the AJCC tumor registry to determine if they provide improved prognostic power compared to current practice. PUBLIC HEALTH RELEVANCE: Melanoma is an aggressive form of skin cancer comprised of still incompletely defined subtypes. The goal of this project is the discovery of markers that improve classification, diagnosis, and stratification for therapy.

描述（由申请人提供）：黑色素瘤是一种侵袭性皮肤癌，其总体发病率和死亡率在全球范围内不断增加。黑色素瘤的临床和组织病理学表现、与紫外线的关系以及流行病学方面存在显着的未解决的复杂性。基于疾病的微观模式将肿瘤分层为“组织遗传学”类型的尝试尚未在临床上得到广泛接受，因为所提出的标准之间存在显着重叠，并且疾病的分类和临床病程之间的关系有限。在过去的十年中，我们对原发性黑色素瘤的研究已经证明了遗传上不同的黑色素瘤亚型，这些亚型与患者种系基因型、发病的解剖部位和日光照射有关。这项工作解决了黑色素瘤之间是否存在有意义的区别的问题，并推动了该领域致力于发现这些差异。这一领域的进一步进展至关重要，因为目前的疗法已被证明无效，部分原因可能是患者亚群的反应未被识别。该提案的目标是建立一个遗传和表型标记框架，定义具有常见机制改变的疾病类别，并提供可用于分类、诊断和识别可能对新兴疗法产生反应的患者群体的标记针对基因改变。为了实现这一目标，我们将从现有 WHO 分类的类别中取样，组建一个由 350 例原发性黑色素瘤组成的表型多样化队列。该发现和培训队列将用于识别新的遗传标记，完善表型评估并根据遗传、临床和组织病理学特征建立分类算法。将验证临时分类算法使用独立的原发性肿瘤队列产生遗传同质亚组的能力，并且将使用第三队列确定这些亚组与疾病结果的关联。最后，我们将仅使用通常收集的临床信息来定义替代标志物，并将其应用于 AJCC 肿瘤登记处的 50,000 个病例，以确定与当前实践相比，它们是否能提供更好的预后能力。公共健康相关性：黑色素瘤是一种侵袭性皮肤癌，由尚未完全定义的亚型组成。该项目的目标是发现可改善分类、诊断和治疗分层的标记物。