Identification and molecular characterization of FGFR4 p.G388R variant signaling in cerebellar hemangioblastomas

小脑血管母细胞瘤中 FGFR4 p.G388R 变异信号的鉴定和分子特征

• 批准号: 10450056
• 负责人: DAVID ZAGZAG
• 金额: $ 23.3万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450056
• 关键词: Address; Age; Alleles; Amino Acids; Angiogenic Factor; Archives; Arginine; Benign; Biological; Blood Cells; Blood Vessels; Cell Nucleus; Cerebellum; Charge; Chromosomal Gain; Chromosome 10; Chromosome 3; Chromosome 6; Chromosome abnormality; Chromosomes; Classification; Clear cell renal cell carcinoma; Codon Nucleotides; Counseling; Databases; Disease; Epidermal Growth Factor Receptor; Excision; Gene Expression; Gene Mutation; Genes; Genetic Counseling; Genetic Transcription; Germ-Line Mutation; Glycine; HIF1A gene; Histologic; Hypermethylation; Hypoxia Inducible Factor; Inherited; Islet Cell Tumor; Lesion; Life Expectancy; Loss of Heterozygosity; Malignant - descriptor; Malignant Neoplasms; Messenger RNA; Molecular; Mutation; Nature; Neoplasms; Neoplastic Stromal Cell; Neuraxis; Online Mendelian Inheritance In Man; Operative Surgical Procedures; Pathogenesis; Pathogenicity; Patients; Pharmacotherapy; Predisposition; Prevalence; Proteins; Recurrence; Renal Cell Carcinoma; Resectable; Risk; Role; Signal Pathway; Signal Transduction; Somatic Mutation; Stat3 protein; Testing; Therapeutic; Transmembrane Domain; Tumor Angiogenesis; Tumor Suppressor Genes; VHL gene; VHL mutation; VHL protein; Variant; Vascular Endothelial Growth Factors; Visceral; Von Hippel-Lindau Syndrome; Work; angiogenesis; base; cohort; exome sequencing; fibroblast growth factor receptor 4; gain of function; genetic analysis; genetic testing; hemangioblastoma; hypoxia inducible factor 1; novel; novel marker; promoter; receptor; tumor; tumorigenesis; ubiquitin-protein ligase

PROJECT SUMMARY Histologically characterized by neoplastic stromal cells and abundant vasculature, hemangioblastomas (HBs) occur as sporadic lesions (~70%, predominantly in the cerebellum) and in familial forms associated with von Hippel-Lindau (VHL) disease, an inherited multisystem tumor disorder characterized by HBs and other benign and malignant visceral neoplasms (e.g., clear cell renal cell carcinoma (RCC)). Central nervous system (CNS) HBs, which are frequently multiple or recurrent in VHL disease, may not be resectable, and an effective drug treatment is not available. Although biallelic inactivation of the VHL tumor suppressor gene by pathogenic mutations, promoter hypermethylation and/or loss of VHL-bearing chromosome 3p25 have been identified in 47% to 64% of both familial (germline mutations) and sporadic (somatic mutations) CNS HBs, the underlying pathogenic mechanisms responsible for HBs remain incompletely understood. By whole exome sequencing of archived VHL disease-associated and sporadic cerebellar HBs and matched cerebellum and/or blood cells (n=23, age 24-63), we found 314 pathogenic and/or likely deleterious mutations (both germline and somatic). In a significant number of cases (14/23, 61%), we identified the germline fibroblast growth factor receptor 4 (FGFR4) p.G388R variant, 8 of which were VHL wild-type and 2 had multiple/recurrent cerebellar HBs; the other 6 cases had both FGFR4 p.G388R and VHL mutations, 1 of which had multiple/recurrent cerebellar HBs and RCC. FGFR4 p.G388R is a pathogenic activating mutation known to enhance basal signal transducer and activator of transcription 3 (STAT3) signaling, resulting in increased HIF-1α mRNA transcription, STAT3- and HIF-1 target gene expression, angiogenesis, and possibly increased tumor susceptibility. We hypothesize that in addition to VHL inactivation, a significant number of VHL disease-associated and sporadic cerebellar HBs harbor germline FGFR4 p.G388R variant that activates STAT3 signaling and target gene expression in these tumors. We also hypothesize that gene promoter hypermethylation (e.g. VHL) and/or chromosomal alterations (e.g., EGFR amplification) may coexist with FGFR4 p.G388R variant and could together contribute to VHL disease-associated and sporadic cerebellar HB pathogenesis. Based on our initial results, we propose (Aim 1a) to validate in a larger cohort of archived cerebellar HBs our novel finding that a significant number of both VHL disease-associated and sporadic HBs harbor germline FGFR4 p.G388R. We also propose (Aim 1b) to define whether FGFR4 p.G388R activates the JAK-STAT-HIF signaling pathway in these tumors and (Aim 2) to demonstrate whether gene promoter hypermethylation and/or chromosomal alterations may co-exist with FGFR4 p.G388R variant and could together contribute to VHL disease-related and sporadic cerebellar HB pathogenesis. We anticipate that our proposed work could have a significant impact on the genetic testing and counseling of patients living with HBs. If successful, our work could also demonstrate a novel biomarker for CNS HB patient classification and potentially targetable mechanisms against CNS HBs.

项目总结 组织学特征为肿瘤间质细胞和丰富的血管，血管母细胞瘤(HBs) 以散发性病变(约70%，主要发生在小脑)和与von相关的家族性形式发生 希佩尔-林道病(Hippel-Lindau，VHL)，一种遗传性多系统肿瘤疾病，以HBs和其他良性疾病为特征 和恶性内脏肿瘤(例如，肾透明细胞癌)。中枢神经系统(CNS) HBs在VHL病中经常是多发或复发的，可能无法切除，是一种有效的药物 目前还没有治疗方法。尽管致病基因VHL肿瘤抑制基因的双等位基因失活 已发现携带VHL的染色体3p25的突变、启动子超甲基化和/或丢失 47%至：家族性(胚系突变)和散发性(体细胞突变)CNS HBs，潜在的 导致HBs的致病机制仍不完全清楚。通过外显子组的全序列测定 与VHL病相关的档案和散发性小脑HBs以及匹配的小脑和/或血细胞 (n=23，年龄24-63岁)，我们发现了314个致病和/或可能的有害突变(包括种系和体细胞)。在……里面 有相当数量的病例(14/23，61%)，我们鉴定出胚系成纤维细胞生长因子受体4 (FGFR4)p.G388R变异，其中8例为VHL野生型，2例为多发性/复发性小脑HBs；另1例 6例同时存在FGFR4p.G388R和VHL突变，其中1例为多发性/复发性小脑HBs和 RCC。FGFR4 p.G388R是一种致病活性突变，可增强基础信号转导和 转录激活子3(STAT3)信号转导，导致HIF-1STAT3和α转录增加 HIF-1靶基因表达、血管生成，并可能增加肿瘤的易感性。我们假设 除了VHL失活外，相当数量的VHL疾病相关和散发性小脑HBs 港湾生殖系FGFR4 p.G388R变异体激活STAT3信号转导和靶基因表达 肿瘤。我们还假设基因启动子高甲基化(例如VHL)和/或染色体改变 (例如，EGFR扩增)可能与FGFR4 p.G388R变体共存，并可能共同导致VHL 疾病相关和散发性小脑HB的发病机制。根据我们的初步结果，我们建议(目标1a) 为了在更大的存档小脑HBs队列中验证我们的新发现，大量的VHL 疾病相关的和散发性的HBs含有生殖系FGFR4 p.G388R。我们还建议(目标1b)定义 FGFR4 p.G388R是否激活这些肿瘤中的JAK-STAT-HIF信号通路以及(目标2) 证明基因启动子超甲基化和/或染色体改变是否可能与 FGFR4 p.G388R变异可能共同导致VHL疾病相关和散发性小脑HB 发病机制。我们预计，我们拟议的工作可能会对基因检测和 为乙肝患者提供咨询服务。如果成功，我们的工作还可能展示一种新的中枢神经系统生物标记物 乙肝患者分类和针对CNS HBs的潜在靶向机制。