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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要组织学特征为肿瘤性基质细胞和丰富的脉管系统，血管母细胞瘤 (HBs) 以散发性病变（约 70%，主要发生在小脑）的形式发生，并以与 von 相关的家族形式出现 Hippel-Lindau (VHL) 病，一种遗传性多系统肿瘤疾病，以 HB 和其他良性肿瘤为特征和恶性内脏肿瘤（例如，透明细胞肾细胞癌（RCC））。 HBs 在 VHL 疾病中经常发生多发或复发，可能无法切除，而有效的药物尽管 VHL 肿瘤抑制基因被致病性双等位基因失活，但尚无治疗方法。突变、启动子高甲基化和/或携带 VHL 的染色体 3p25 缺失已在 47% 至 64% 的家族性（种系突变）和散发性（体细胞突变）CNS HBs 是潜在的通过全外显子组测序，HBs 的致病机制仍不完全清楚。存档的 VHL 疾病相关和散发的小脑 HB 以及匹配的小脑和/或血细胞（n=23，年龄 24-63），我们发现了 314 个致病性和/或可能有害的突变（包括种系突变和体细胞突变）。在大量病例（14/23，61%）中，我们鉴定出了种系成纤维细胞生长因子受体 4 (FGFR4) p.G388R 变体，其中 8 个为 VHL 野生型，2 个具有多个/复发性小脑 HB； 6 例同时具有 FGFR4 p.G388R 和 VHL 突变，其中 1 例具有多发性/复发性小脑 HBs 和 FGFR4 p.G388R 是一种致病性激活突变，已知可增强基础信号转导和转录激活剂 3 (STAT3) 信号传导，导致 HIF-1α mRNA 转录增加，STAT3- 和 HIF-1 靶标基因表达、血管生成，并可能增加肿瘤易感性。除了 VHL 失活外，大量 VHL 疾病相关和散发的小脑 HB 含有种系 FGFR4 p.G388R 变体，可激活这些细胞中的 STAT3 信号传导和靶基因表达我们还经历了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，并可能共同促成 VHL 根据我们的初步结果，我们提出（目标 1a）。为了在更大的存档小脑 HB 队列中验证我们的新发现，即大量的 VHL 疾病相关和散发的 HBs 含有种系 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）证明基因启动子高甲基化和/或染色体改变是否可以与 FGFR4 p.G388R 变异可能共同导致 VHL 疾病相关和散发性小脑 HB 我们预计我们提出的工作可能会对基因检测和发病机制产生重大影响。如果成功的话，我们的工作还可以展示一种新的中枢神经系统生物标志物。 HB 患者分类和针对 CNS HB 的潜在目标机制。