Integration of Clinical and Molecular Biomarkers for Melanoma Survival

黑色素瘤生存的临床和分子生物标志物的整合

• 批准号: 10188447
• 负责人: MARIANNE BERWICK
• 金额: $ 198.72万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188447
• 关键词: Aberrant DNA Methylation; Adjuvant Therapy; Affect; Aggressive behavior; American Joint Committee on Cancer; BRAF gene; Bioinformatics; Biological Assay; Biological Markers; Biology; CD3 Antigens; CD8B1 gene; CDKN2A gene; Candidate Disease Gene; Characteristics; Clinic; Clinical; Copy Number Polymorphism; CpG Island Methylator Phenotype; DNA; DNA Markers; DNA Methylation; DNA methylation profiling; Data; Data Set; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease; Drug Targeting; Epidemiology; Event; FOXP3 gene; Frequencies; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genomics; Goals; Heterogeneity; Immune; Individual; Institution; Joints; Literature; Malignant Neoplasms; Messenger RNA; Methods; Methylation; MicroRNAs; Molecular; Mutation; NF1 mutation; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; PTEN gene; Pathologic; Patient-Focused Outcomes; Patients; Predictive Factor; Prior Therapy; Process; Prognosis; Prognostic Marker; Proteins; RNA marker; Reproducibility; Research Personnel; Role; Somatic Mutation; Specimen; Stage at Diagnosis; Staging; Stains; Stratification; Subgroup; TNM; Testing; Time; Tissues; Training; Translating; Triage; Tumor Tissue; Validation; aggressive therapy; base; care outcomes; clinical biomarkers; clinical care; clinical practice; cohort; high risk; improved; mRNA Expression; melanoma; melanoma biomarkers; molecular marker; molecular subtypes; mortality; nano-string; novel; outcome prediction; personalized care; predictive signature; prognostic; prognostic of survival; prognostic signature; programmed cell death ligand 1; programmed cell death protein 1; programs; protein expression; response; standard of care; survival outcome; survival prediction; targeted sequencing; tumor; tumor heterogeneity

Program Project Abstract/Summary We have brought together 12 institutions in order to promote a better understanding of the biology of melanoma and how that affects an individual’s survival. Our hypothesis is that primary melanomas will have molecular and clinical features that will allow the stratification of melanoma tumors at AJCC TNM Stages IIA/IIB/IIC/IIIA/IIIB, where there is little effective adjuvant therapy, into those with a good prognosis and those with poor prognosis. The current mortality rate for individuals diagnosed at these stages ranges between 18- 47% for Stages IIA/IIB/IIC and 32-78% for Stage IIIA/IIIB patients. The ability to improve clinical care and patient outcomes for these patients might be achieved by focusing on the identification and prioritization of biomarkers – both molecular and clinical – that might triage high risk patients for new adjuvant therapies. In this study, we will identify somatic tumor mutations, CNVs, an immune profile, methylation profiles, and microRNA/mRNA signatures in primary melanoma that are associated with prognosis, with the ultimate intent of translating this information into the clinic to personalize care. Currently, there is a dearth of studies in the melanoma field looking at epidemiologic/genomic factors and melanoma survival. In order to identify, confirm and develop such biomarkers, we have brought together 9 cohorts of melanoma patients at AJCC TNM stages IIA/IIB/IIC/IIIA/IIIB, comprising 1000 individuals, 500 of whom have died from their disease as of 2012 and 500 whom have lived at least 5 years. Patients will be frequency matched for stage. As we integrate data from multiple platforms, we will randomly divide the dataset into a training set (660 tumors, half aggressive and half non-aggressive) and a validation set (340 tumors, half aggressive and half non-aggressive). Significant findings in the training set will be replicated in the validation set. These patients have all been treated using standard-of-care surgery. All patients in this study will have adequate tumor tissue, germline DNA and clinical, pathologic and demographic information recorded. Our objective is to identify prognostic biomarkers associated with survival. The goal is to identify patients for whom more aggressive therapy prior to developing metastases would be relevant, that is would make a difference to their survival. Our central hypothesis is that melanoma prognosis is largely determined early in tumor development and that DNA and RNA markers, combined with clinicopathologic and protein characteristics in primary melanoma will add information to outcome prediction beyond the pathologic features used in AJCC tumor staging. We are taking an integrative approach to take advantage of and organize the large amount of information generated from each project. Such information will be available to clinicians and other investigators as soon as possible.

计划项目摘要/摘要 我们汇集了 12 个机构，以促进人们更好地了解生物的生物学 黑色素瘤及其如何影响个体的生存。我们的假设是原发性黑色素瘤将具有 允许在 AJCC TNM 分期对黑色素瘤肿瘤进行分层的分子和临床特征 IIA/IIB/IIC/IIIA/IIIB，对于预后良好的患者和那些几乎没有有效辅助治疗的患者 预后不良。目前在这些阶段诊断的个体的死亡率在 18- IIA/IIB/IIC 期患者为 47%，IIIA/IIIB 期患者为 32-78%。改善临床护理和 这些患者的治疗结果可以通过重点识别和优先考虑来实现 分子和临床生物标志物可能会对高风险患者进行新辅助治疗的分类。 在这项研究中，我们将鉴定体细胞肿瘤突变、CNV、免疫谱、甲基化谱和 原发性黑色素瘤中与预后相关的 microRNA/mRNA 特征，其最终目的 将这些信息转化为诊所以提供个性化护理。目前，这方面的研究还比较缺乏 黑色素瘤领域着眼于流行病学/基因组因素和黑色素瘤生存。为了识别、确认 并开发此类生物标志物，我们汇集了 9 组处于 AJCC TNM 阶段的黑色素瘤患者 IIA/IIB/IIC/IIIA/IIIB，由 1000 人组成，截至 2012 年，其中 500 人死于该病，500 人死于该病 已经活了至少 5 年的人。患者将根据阶段进行频率匹配。当我们整合数据时 多个平台，我们将数据集随机划分为训练集（660 个肿瘤，一半为侵袭性肿瘤，一半为侵袭性肿瘤） 非攻击性）和验证集（340 个肿瘤，一半为攻击性，一半为非攻击性）。重要的 训练集中的发现将复制到验证集中。这些患者均已接受过治疗 标准护理手术。本研究中的所有患者都将有足够的肿瘤组织、种系 DNA 和临床、 记录病理和人口统计信息。 我们的目标是确定与生存相关的预后生物标志物。目标是识别患者 在发生转移之前进行更积极的治疗是相关的，也就是说， 他们的生存差异。我们的中心假设是黑色素瘤的预后很大程度上取决于早期 肿瘤的发展和 DNA 和 RNA 标记，结合临床病理学和蛋白质 原发性黑色素瘤的特征将为病理特征之外的结果预测添加信息 用于 AJCC 肿瘤分期。我们正在采取综合方法来利用和组织 每个项目都会产生大量信息。这些信息将提供给临床医生和 其他调查人员尽快进行调查。