Prognostic markers in metastatic melanoma

转移性黑色素瘤的预后标志物

• 批准号: 8134478
• 负责人: Bonnie Elyssa GouldRothberg
• 金额: $ 10.89万
• 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/8134478
• 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; public health relevance; research study; response; skills; tumor

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The overall outcome for metastatic melanoma is dismal; approximately 8700 Americans annually die from melanoma and the median survival following the diagnosis of melanoma metastases is less than 1 year. Yet, at the same time, about 25% of patients with metastatic melanoma will survive 2 or more years with their cancer and 5% will live for 5 years or more. Being able to predict, at the time that metastatic melanoma is first detected by physicians, which patients will experience a rapid decline in their health and which patients will enjoy a longer survival in spite of their disease has the potential to improve the care for all patients with metastatic melanoma.

描述（由申请人提供）：该提案描述了一个为期 5 年的分子癌症流行病学学术职业发展培训计划。首席研究员刚刚在耶鲁大学完成了流行病学和公共卫生博士学位，这是她在 20 世纪 90 年代完成的医学博士培训的补充。在耶鲁大学病理学和流行病学系之间独特的跨部门合作背景下，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对 192 名原发性黑色素瘤患者进行队列研究，以表征选定的癌症相关蛋白的差异表达，执行多变量统计算法来开发多标志物预后模型，并在 246 例原发性黑色素瘤病例的单独队列中验证该模型。她现在寻求通过以下方式扩展自己作为分子癌症流行病学家的能力：1) 获得以 DNA 为中心的实验室技能，用于分析种系和基于肿瘤的体细胞遗传变异的水平 2) 扩大对可用于构建综合预后模型的多变量统计方法的熟悉程度，以及 3 ) 获得收集调查数据以及处理和归档生物样本的流行病学现场工作的额外经验。 该计划将继续首席研究员在黑色素瘤预后方面的独特跨学科培训。 David L. Rimm 博士，病理学教授兼耶鲁大学病理学组织服务主任，Susan T. Mayne 博士，流行病学和公共卫生教授，耶鲁大学癌症中心人口科学副主任兼癌症预防项目负责人和控制研究计划将共同指导首席研究员的科学发展。 Rimm 博士是组织微阵列和癌症生物标志物领域公认的领导者，也是使用免疫组织化学表征蛋白质表达水平的自动定量分析 (AQUA(R)) 的发明者。 Mayne 博士自 1987 年以来一直负责癌症流行病学研究，包括肺癌、头颈癌、乳腺癌、食道癌、胃癌、胰腺癌和子宫内膜癌的病例对照或基于病例的研究。资深生物信息学家 Robert L. Camp 博士将在统计分析阶段提供额外指导。 研究重点是为新诊断的转移性黑色素瘤患者开发基于分子的多标志物预后模型。转移性黑色素瘤总体预后较差，中位生存期<12个月。然而，在临床诊断出转移性疾病后，25% 的个体确实存活了 2 年或更长时间，约 5% 的个体将存活 5 年或更长时间。区分转移性黑色素瘤患者亚组的能力可以优化临床患者护理。过去 25 年没有发生变化，目前只有少数临床病理变量可作为经过验证的预后因素，并且最佳多变量模型与结果的显着预测误差相关。该提案的目的是利用在耶鲁-纽黑文医院接受转移性黑色素瘤切除术的两个独立、注释明确的患者队列，生成并验证转移性黑色素瘤的预后模型，该模型整合了临床病理学、遗传和表达数据。具体目标包括：1）根据临床病理变量、种系遗传变异以及基于肿瘤的体细胞突变和已知与黑色素瘤生物学相关的选定候选基因的蛋白质表达，建立转移性黑色素瘤死亡时间的综合预后模型。一项回顾性 Discovery 队列，由 1959 年至 1994 年间在耶鲁纽黑文医院接受转移性黑色素瘤切除术的 217 名患者组成，2) 验证转移性黑色素瘤1995-2008 年在耶鲁-纽黑文医院切除的转移性黑色素瘤患者的独立回顾性队列中的黑色素瘤预后模型。 拟议的实验包括耶鲁大学黑色素瘤转移发现（1959-1994）和验证（1995-2008）队列的组装和临床注释，进行湿台实验以收集选定分子候选物的暴露信息以及执行基本生存分析以及高阶多元统计方法来构建转移性黑色素瘤的多标志物预后模型。除了先前在 Discovery 队列中收集的 80 种候选蛋白以及 B-RAF 和 N-RAS 体细胞突变的表达谱外，该提案还将支持表征 25 种其他蛋白的差异表达、10 种基因的体细胞突变和种系遗传变异的工作10个基因。候选者将从已发表的证明与黑色素瘤转移相关的数据中选出。该提案还计划评估生活方式选择（例如体重指数、吸烟和饮酒）与该人群生存的关系。据我们所知，该提案将是首次尝试开发符合 REMARK 标准的转移性黑色素瘤预后模型，其中包含分子暴露。 耶鲁大学病理学系为拟议的研究提供了理想的环境。除了使用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研究人员的互动。 PI 还将参与该机构的黑色素瘤 SPORE 研究计划（Ruth Halaban，PI），并受益于耶鲁大学对个性化癌症治疗的机构承诺，并聘请 Thomas Lynch 博士担任新癌症医院的主治医师。 公共卫生相关性：转移性黑色素瘤的总体结果令人沮丧；每年约有 8700 名美国人死于黑色素瘤，诊断出黑色素瘤转移后的中位生存期不到 1 年。然而，与此同时，约 25% 的转移性黑色素瘤患者将存活 2 年或更长的时间，5% 的患者将存活 5 年或更长的时间。在医生首次发现转移性黑色素瘤时，能够预测哪些患者的健康状况将迅速恶化，哪些患者尽管患有疾病，但仍将享有更长的生存期，这有可能改善对所有患者的护理患有转移性黑色素瘤。