Molecular and immunologic evolution of melanomas from pre-neoplastic lesions

肿瘤前病变黑色素瘤的分子和免疫学进化

• 批准号: 10005924
• 负责人: Boris C. Bastian
• 金额: $ 95.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005924
• 关键词: Algorithms; Automobile Driving; Behavior; Benign; Biological; Biological Markers; Cancer Detection; Cessation of life; Clinical; Complement; Development; Diagnostic; Disease; Early treatment; Equilibrium; Event; Evolution; Goals; Immune response; Immunologics; Individual; Indolent; Investigation; Lesion; Light; Malignant - descriptor; Malignant Neoplasms; Melanocytic Neoplasm; Methods; Molecular; Molecular Analysis; Mutation; Outcome; Patients; Primary Lesion; Prognostic Marker; Risk stratification; Taxonomy; Testing; Translating; Tumor-infiltrating immune cells; Validation; advanced disease; base; cancer genome; cancer prevention; cohort; diagnostic biomarker; follow-up; genetic evolution; high risk; improved; improved outcome; insight; melanoma; multiple omics; neoplastic; neoplastic cell; prognostic; screening; sound; tumor; tumor-immune system interactions

Project Summary/Abstract Tremendous advances in the molecular analysis of melanomas and their immune microenvironment have provided mechanistic insights, which in turn have translated into remarkable improvements to treat and even cure patients with advanced disease. However, many patients still succumb to their disease, in part because treatment starts too late. Identifying patients in need of systemic treatment earlier and removing pre-neoplastic lesions before they evolve into cancer are promising effective ways to reduce melanoma-related deaths. Current screening methods can detect lesions with a broad spectrum of natural behavior-- from those with lethal potential to the completely benign. There is an urgent need to develop precision molecular tests to: (1) Distinguish between benign and malignant lesions (i.e., diagnostic biomarkers); (2) Differentiate biologically indolent versus aggressive tumors in need of additional treatment (i.e., prognostic biomarkers); (3) Identify high-risk individuals who should be screened (i.e., screening biomarkers). My group is performing multi-omics studies on primary lesions to study the earliest molecular and cellular events associated with melanoma initiation and evolution to obtain key insights that are essential to improve risk stratification of early stage cancers, cancer prevention and detection. Characterizing the genetic evolution of main melanoma subtypes as they develop from their respective pre-neoplastic lesions is one major goal of this proposal, as is developing a biomarker-based taxonomy, which will serve as framework for developing significantly advanced diagnostic and prognostic algorithms. Studies of the tumor genome will be complemented by characterization of the composition and functional state of immune cell infiltrates during melanoma evolution to shed light on the interaction between the immune cell infiltrate and tumor cells. The combined analysis of tumor genomes and host response will reveal key mechanisms driving elimination, equilibrium, and ultimate escape and allow us to extract biomarkers, which will undergo validation in patients with known outcomes with the goal to develop clinically sound tests. Specifically, we will formulate candidate algorithms that can (i) better anticipate metastatic dissemination than current methods and (ii) predict whether a pre-neoplastic lesion is likely to progress to melanoma, and validate them using patient cohorts with known follow-up information.

项目概要/摘要 黑色素瘤及其免疫微环境的分子分析取得巨大进展 提供了机械见解，这反过来又转化为显着的改进 治疗甚至治愈晚期疾病的患者。然而，许多患者仍然屈服于他们的 疾病，部分原因是治疗开始得太晚。识别需要系统治疗的患者 在肿瘤前期病变演变成癌症之前尽早去除它们是有希望的有效方法 减少与黑色素瘤相关的死亡。目前的筛查方法可以广泛检测病变 自然行为的范围——从具有致命潜力的行为到完全良性的行为。有一个 迫切需要开发精密分子测试来： （1）区分良性和恶性病变（即诊断生物标志物）； (2) 区分需要额外治疗的生物学惰性肿瘤和侵袭性肿瘤 （即预后生物标志物）； (3) 确定应筛查的高风险个体（即筛查生物标志物）。 我的小组正在对原发性病变进行多组学研究，以研究最早的分子和 与黑色素瘤发生和进化相关的细胞事件以获得关键见解 对于改善早期癌症的风险分层、癌症预防和检测至关重要。 描述主要黑色素瘤亚型从各自发展而来的遗传进化特征 肿瘤前病变是该提案的一个主要目标，开发基于生物标记的分类法也是如此， 它将作为开发显着先进的诊断和预后的框架 算法。肿瘤基因组的研究将通过成分的表征来补充 黑色素瘤进化过程中免疫细胞浸润和功能状态揭示了相互作用 免疫细胞浸润和肿瘤细胞之间。肿瘤基因组和宿主的联合分析 反应将揭示驱动消除、平衡和最终逃逸的关键机制，并允许 我们提取生物标志物，这些生物标志物将在具有已知结果的患者中进行验证，以达到目标 开发临床上合理的测试。具体来说，我们将制定候选算法，能够（i）更好 与现有方法相比，预测转移性播散，并且（ii）预测肿瘤前期是否存在 病变可能进展为黑色素瘤，并使用具有已知随访情况的患者队列进行验证 信息。