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

> **NIH NIH R21** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $232,969

## Abstract

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 p...

## Key facts

- **NIH application ID:** 10450056
- **Project number:** 5R21CA263402-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** DAVID ZAGZAG
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $232,969
- **Award type:** 5
- **Project period:** 2021-07-12 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450056

## Citation

> US National Institutes of Health, RePORTER application 10450056, Identification and molecular characterization of FGFR4 p.G388R variant signaling in cerebellar hemangioblastomas (5R21CA263402-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10450056. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*