Prognostic markers in metastatic melanoma

转移性黑色素瘤的预后标志物

• 批准号: 8324664
• 负责人: Bonnie Elyssa GouldRothberg
• 金额: $ 10.4万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8324664
• 关键词: Address; Adverse effects; Alcohol consumption; Algorithms; American; Archives; BAY 54-9085; Basic Science; Behavior; Biological Assay; Biological Markers; Biology; Body mass index; Breast; Camping; Cancer Control Research Program; Cancer Hospital; Cancer Prognosis; Candidate Disease Gene; Caring; Case-Control Studies; Categories; Cessation of life; Characteristics; Clinic; Clinical; Collaborations; DNA; Data; Data Collection; Data Set; Development; Diagnosis; Diet; Disease; Doctor of Philosophy; Endometrial Carcinoma; Epidemiologist; Epidemiology; Equipment; Excision; Faculty; Familiarity; Formalin; Gene Expression; Genes; Genetic; Genetic Variation; Genome; Goals; Head and neck structure; Health; Heterogeneity; Hospitals; Immunofluorescence Immunologic; Immunohistochemistry; Individual; Institution; Interferons; Interleukin-2; Laboratories; Life; Life Style; Lung; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of pancreas; Medical Records; Mentors; Metastatic Melanoma; Methods; Modeling; Molecular; Molecular Epidemiology of Cancer; Molecular Profiling; Mutation; NRAS gene; Neoplasm Metastasis; Newly Diagnosed; Oncogenes; Outcome; Paraffin Embedding; Pathology; Patient Care; Patients; Performance; Pharmacogenomics; Phase; Physical activity; Physicians; Population; Population Sciences; Post-Translational Protein Processing; Principal Investigator; Prognostic Factor; Prognostic Marker; Program Development; Proteins; Public Health; Publishing; Quality of life; Regimen; Research; Research Personnel; Resected; Services; Solid Neoplasm; Somatic Mutation; Source; Statistical Methods; Subgroup; Surveys; Survival Analysis; Systemic Therapy; Therapeutic; Time; Tissue Microarray; Tissues; Tobacco use; Training; Training Programs; Translations; Tumor Markers; Ultraviolet Rays; Universities; Validation; Work; Yale Cancer Center; base; cancer epidemiology; cancer prevention; cancer therapy; career; case control; clinical Diagnosis; cohort; collected works; epidemiology study; experience; improved; malignant stomach neoplasm; melanoma; molecular phenotype; outcome forecast; professor; prognostic; programs; protein B; protein expression; research study; response; skills; tumor

This proposal describes a 5-year training program for the development of an academic career in Molecular Cancer Epidemiology. The Principal Investigator has just completed a PhD in Epidemiology and Public Health at Yale University, supplementing the MD training she completed in the 1990s. In the context of a unique inter-departmental collaboration between the Pathology and Epidemiology departments at Yale, her dissertation research focused on characterizing the differential expression of selected cancer-related proteins using immunofluorescence-based immunohistochemical methods on a cohort of 192 primary melanoma patients, on executing multivariate statistical algorithms to develop a multi-marker prognostic model and validating the model in a separate cohort of 246 cases of primary melanoma. She now seeks to expand her capabilities as a molecular cancer epidemiologist by 1) acquiring DNA-focused laboratory skills for assaying levels of germline and tumor-based somatic genetic variation 2) expanding her familiarity with multivariate statistical methods useful for building integrated prognostic models and 3) gaining additional experience with epidemiologic field work for collecting survey data and for handling and archiving biospecimens. This program will continue the Principal Investigator's unique cross-disciplinary training in melanoma prognosis. Dr. David L. Rimm, Professor of Pathology and Director of Yale Pathology Tissue Services, and Dr. Susan T. Mayne, Professor of Epidemiology and Public Health, Associate Director for Population Sciences at the Yale Cancer Center and Program Leader for the Cancer Prevention and Control Research Program will jointly co-mentor the Principal Investigator's scientific development. Dr. Rimm is a recognized leader in the field of tissue microarrays and cancer biomarkers and is the inventor of Automated Quantitative Analysis (AQUA(R)) for characterizing levels of protein expression using immunohistochemistry. Dr. Mayne has directed cancer epidemiology studies since 1987, including case-control or case-based studies of lung, head and neck, breast, esophageal, gastric, pancreatic and endometrial cancers. Dr. Robert L. Camp, an established bioinformatician, will provide additional guidance during the statistical analysis phase. Research will focus on developing a molecularly-based multi-marker prognostic model for patients with newly-diagnosed metastatic melanoma. Metastatic melanoma has an overall poor prognosis with a median survival of <12 months. Yet, 25% of individuals do survive 2 or more years and ~5% will survive 5 or more years following the clinical diagnosis of metastatic disease. The ability to discriminate among subgroups of metastatic melanoma patients could optimize patient care in the clinic. Unchanged over the past 25 years, only a few clinicopathologic variables presently serve as validated prognostic factors and best multivariate models are associated with substantial prediction error for outcome. The objective of this proposal is to generate and validate a prognostic model for metastatic melanoma that integrates clinicopathologic, genetic, and expression data, utilizing two independent, well-annotated cohorts of patients who underwent metastatic melanoma resections at Yale-New Haven Hospital. The Specific Aims include: 1) to build an integrated prognostic model for time to death from metastatic melanoma from clinicopathologic variables, germline genetic variation, as well as tumor-based somatic mutations and protein expression for selected candidate genes of known relevance to melanoma biology in a retrospective Discovery cohort of 217 patients who underwent a metastatic melanoma resection at Yale-New Haven Hospital during 1959-1994 and 2) to validate the metastatic melanoma prognostic model in an independent retrospective cohort of patients with metastatic melanoma resected at Yale-New Haven Hospital during 1995-2008. Proposed experiments include the assembly and clinical annotation of both the Yale Melanoma Metastasis Discovery (1959-1994) and Validation (1995-2008) cohorts, the performance of wet-bench experiments to collect exposure information for selected molecular candidates and the execution of basic survival analyses as well as higher-order multivariate statistical methods to construct a multi-marker prognostic model for metastatic melanoma. In addition to the expression profiles for 80 candidate proteins and B-RAF and N-RAS somatic mutations previously collected on the Discovery cohort, this proposal will support work to characterize differential expression for 25 additional proteins, somatic mutations for 10 genes and germline genetic variation for 10 genes. Candidates will be selected from published data demonstrating relevance to melanoma metastasis. This proposal also plans to evaluate the association of lifestyle choices such as body mass index, and tobacco and alcohol use with survival in this population. This proposal will be, to the best of our knowledge, the first attempt to develop a REMARK-compliant prognostic model for metastatic melanoma that incorporates molecular exposures. The Pathology Department at Yale University provides an ideal setting for the proposed research. In addition to access to state-of-the-art facilities and equipment, she will also benefit from interactions with prominent junior and senior cancer investigators among the faculty. The PI will also participate in the Institution's Melanoma SPORE research program (Ruth Halaban, PI) and benefit from Yale's institutional commitment to personalized cancer therapy, supported by its hiring of Dr. Thomas Lynch as Physician-in-Chief of the new cancer hospital.

该建议描述了一项为期5年的培训计划，以开发分子癌流行病学的学术生涯。首席研究人员刚刚在耶鲁大学完成了流行病学和公共卫生博士学位，并补充了她在1990年代完成的MD培训。在耶鲁大学病理学和流行病学部门之间独特的部门间协作的背景下，她的论文研究重点是使用基于免疫荧光的免疫组织化学方法来表征所选癌症相关蛋白质的差异表达，这是在192个主要蜂窝质量模型上，用于执行五进制的Algormant Angormant Angormant Angormant Angormand Angormant Angormoard Angormoard Algormant Angormoard Angormoma protigation Algormant Angormant Angormant Angormant Angormant Angormant Angormant Angormant Angormant Algormant Angormant Algormant Angormant and Grounter a。在另一组246例原发性黑色素瘤中。她现在试图通过1）通过1）获得以DNA为中心的实验室技能来扩展自己作为分子癌的流行病学家，以测定种系和基于肿瘤的体细胞遗传变异的水平2）扩展她对多变量统计方法的熟悉程度，可用于构建综合预后模型的多变量统计方法，并在构建档案中进行培训和档案的其他经验，以供档案进行研究，并进行培训，并进行了研究。 该计划将继续主要研究者在黑色素瘤预后中的独特跨学科培训。病理学教授兼耶鲁病理组织服务主任David L. Rimm博士以及耶鲁大学癌症中心的流行病学和公共卫生教授Susan T. Mayne博士，癌症预防和控制研究计划的计划负责人副主任将共同共同共同委员会。 RIMM博士是组织微阵列和癌症生物标志物领域的公认领导者，并且是自动定量分析（Aqua（R））的发明者，用于使用免疫组织化学表征蛋白质表达水平。自1987年以来，Mayne博士一直在指导癌症流行病学研究，包括病例对照或基于病例的肺，头颈，乳房，乳房，食管，胃，胰腺和子宫内膜癌。既定的生物信息学家罗伯特·L·坎普（Robert L. Camp）博士将在统计分析阶段提供额外的指导。 研究将着重于为新诊断的转移性黑色素瘤患者开发基于分子的多标记预后模型。转移性黑色素瘤的总体预后不良，中位存活率<12个月。然而，在转移性疾病的临床诊断后，有25％的人能够生存2年或更长时间，约5％将在5％或更长时间内生存。区分转移性黑色素瘤患者亚组的能力可以优化诊所的患者护理。在过去的25年中，只有少数临床病理变量目前充当经过验证的预后因素，而最佳多元模型与最佳预测误差有关。该提案的目的是为转移性黑色素瘤生成和验证一种整合临床病理，遗传和表达数据的预后模型，利用在耶鲁 - 新避风港在耶鲁大学接受转移性黑色素瘤切除术的患者的两名独立，良好的众多同类。具体目的包括：1）建立一个综合预后模型，以从临床病理变量的转移性黑色素瘤到死亡时间，生殖线遗传变异以及基于肿瘤的体细胞突变和蛋白质突变和蛋白质的表达和蛋白质的表达，以使已知与黑素瘤相关的已知相关性的候选候选基因在回顾性发现患者中，而在217个梅伦患者中，梅兰在217个患者中都有梅兰的生物学，并1959 - 1994年和2）在1995 - 2008年期间，在耶鲁 - 新避风港医院切除的转移性黑色素瘤患者的独立回顾性人群中，验证了转移性黑色素瘤的预后模型。 提出的实验包括Yale黑色素瘤转移发现（1959-1994）和验证（1995-2008）的组装和临床注释，湿台实验的性能，以收集所选分子候选者的暴露信息，以收集基本候选者以及基本生存分析的执行以及构建近等的跨性别方法，以构建一个跨度的方法。黑色素瘤。除了先前在发现队列上收集的80种候选蛋白质以及B-RAF和N-RAS的体细胞突变的表达谱外，该建议还将支持表征25种其他蛋白质的差异表达，10个基因的体细胞突变和10个基因的生殖线遗传变异。候选人将从已发布的数据中选择，证明与黑色素瘤转移相关。该提案还计划评估生活方式选择的关联，例如体重指数，烟草和酒精的使用以及该人群的生存。据我们所知，该提议将是开发符合分子暴露的转移性黑色素瘤预后模型的首次尝试。 耶鲁大学病理学系为拟议研究提供了理想的环境。除了获得最先进的设施和设备外，她还将受益于与教师中著名的初级和高级癌症调查员的互动。 PI还将参加该机构的黑色素瘤孢子研究计划（Ruth Halaban，PI），并从耶鲁大学对个性化癌症治疗的机构承诺中受益，并在聘请了新癌症医院的医师托马斯·林奇（Thomas Lynch）博士的支持下得到了支持。