Genetic Predictors of Ameloblastoma Behavior

成釉细胞瘤行为的遗传预测因子

• 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
• 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

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.

项目摘要 牙源性肿瘤代表了一系列具有不同形态、临床表现 和治疗，尽管与牙齿发育和解剖学相关的共性。的 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，并且治疗选择在很大程度上限于手术的程度，这可能导致 毁容，造成言语和吞咽功能问题，并不总是治愈。 最近的研究表明，至少在这些肿瘤中的一些中存在复发性基因组事件。我们 已经发现SMO（最常见的是SMO-L412F）中的激活突变，SMO是刺猬蛋白的一部分， 在促分裂原活化蛋白激酶（MAPK）途径（最常见的BRAF-V600 E）中 超过80%的成釉细胞瘤其他人以前发现PTCH 1种系失活，也是 与Gorlin综合征（痣样）相关的角化囊性牙源性肿瘤中的Hedgehog通路 基底细胞癌综合征）。这些途径是药物，我们假设，一个新的 牙源性肿瘤的诊断分类和治疗的范例可以通过 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学相似的肿瘤， 诊断，以确定驱动突变和致癌途径。使用突变和 表达谱，我们将创建一个新的分类系统牙源性肿瘤。我们将 从携带复发性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FGFR 2。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 阻力