Genetic Predictors of Ameloblastoma Behavior

成釉细胞瘤行为的遗传预测因子

基本信息

批准号：
10183221
负责人：
JONATHAN R POLLACK
金额：
$ 43.68万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-12 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183221
关键词：
Address Adult African Ameloblastic Carcinoma Ameloblastic Fibroma Ameloblastoma Ameloblasts Anatomy Archives Area BRAF gene Basal Cell Nevus Syndrome Behavior Biological Biological Markers Biology Cell Culture Techniques Cell Line Cells Classification Clinical Clinical Management Clinical Treatment Clinical Trials Deglutition Dental Enamel Dependence Deposition Development Diagnosis Diagnostic Disease Management Drug resistance Embryo Erinaceidae Ethnic Origin Event Excision FGFR2 gene Funding Gene Targeting Genetic Genomics Goals Hair Jaw Jordan KRAS2 gene Keratocyst Lead MEK inhibition MEKs Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Mandible Maryland Maxilla Medical Mitogen-Activated Protein Kinases Modeling Molecular Morphology Mutate Mutation Neoadjuvant Therapy Neoplasm Metastasis Neoplasms Odontogenic Tumors Odontoma Oncogenic Operative Surgical Procedures Organ Pathologist Pathway interactions Patients Pharmacology Pharmacology Study Pilot Projects Play Population RNA Interference Race Recurrence Rehabilitation therapy Research Research Personnel Resistance Role Site Speech Study models System Tissues Tooth structure Tumor Markers Uganda United States Work base cohort driver mutation drug sensitivity exome sequencing experience genetic analysis genetic predictors inhibitor/antagonist insight molecular marker neglect novel patient stratification personalized medicine preclinical study reconstruction response small molecule inhibitor smoothened signaling pathway targeted treatment transcriptome sequencing translational cancer research tumor tumor behavior

项目摘要

PROJECT SUMMARY Odontogenic tumors represent a spectrum of entities with differing morphologies, clinical presentations and treatments, despite commonalities in association with tooth development and anatomy. The complexity of this classification system is challenging for most pathologists, who rarely see these tumors, and the treatment options are largely limited to the extent of surgery, which can result in disfigurement, create functional problems with speech and swallowing, and is not always curative. Recent studies suggest that there are recurrent genomic events in at least some of these tumors. We have discovered activating mutations in SMO (most commonly SMO-L412F), part of the Hedgehog pathway, and in the mitogen-activated protein kinase (MAPK) pathway (most commonly BRAF-V600E) in over 80% of ameloblastomas. Others had previously found PTCH1 germline inactivation, also part of the Hedgehog pathway, in keratocystic odontogenic tumors associated with Gorlin syndrome (nevoid basal cell carcinoma syndrome). These pathways are druggable and we hypothesize that a new paradigm for the diagnostic classification and treatment of odontogenic tumors can be generated with genetic analysis. We will conduct whole-exome sequencing and transcriptome sequencing of odontogenic tumors, focusing on ameloblastoma, keratocystic odontogenic tumors and other morphologically-similar diagnoses, to identify driver mutations and oncogenic pathways. Using both the mutation and expression profiles, we will create a novel classification system for odontogenic neoplasms. We will create multiple new ameloblastoma cell lines from patient material bearing recurrent driver mutations, including BRAF, SMO, KRAS, and FGFR2. These new cell culture models will enable us to examine the response to gene targeted therapies, as well as to anticipate likely mechanisms of therapy resistance.

项目概要牙源性肿瘤代表一系列具有不同形态、临床表现的实体尽管与牙齿发育和解剖学有关的共性，但治疗方法仍然存在。这这种分类系统的复杂性对大多数病理学家来说是一个挑战，他们很少看到这些肿瘤，治疗选择很大程度上限于手术范围，这可能会导致毁容，造成言语和吞咽功能问题，而且并不总是有疗效。最近的研究表明，至少在其中一些肿瘤中存在反复出现的基因组事件。我们发现了 SMO（最常见的是 SMO-L412F）（刺猬的一部分）的激活突变途径，以及丝裂原激活蛋白激酶 (MAPK) 途径（最常见的是 BRAF-V600E）超过 80% 的成釉细胞瘤。其他人之前发现 PTCH1 种系失活，也是 Hedgehog 通路，在与 Gorlin 综合征（痣样痣）相关的角化囊性牙源性肿瘤中基底细胞癌综合征）。这些途径是可药物化的，我们假设有一种新的途径可以生成牙源性肿瘤的诊断分类和治疗范例遗传分析。我们将进行牙源性肿瘤的全外显子组测序和转录组测序，专注于成釉细胞瘤、角化囊性牙源性肿瘤和其他形态相似的肿瘤诊断，以确定驱动突变和致癌途径。同时使用突变和表达谱，我们将为牙源性肿瘤创建一个新的分类系统。我们将从带有反复驱动突变的患者材料中创建多个新的成釉细胞瘤细胞系，包括 BRAF、SMO、KRAS 和 FGFR2。这些新的细胞培养模型将使我们能够检查对基因靶向治疗的反应，以及预测可能的治疗机制反抗。