Role of LRRK2 in IDH-Mutant Grade 4 Astrocytomas: Oncogene or Tumor Suppressor? - European Medical Journal

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Role of LRRK2 in IDH-Mutant Grade 4 Astrocytomas: Oncogene or Tumor Suppressor?

2 Mins
Neurology
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Authors:
Michele Persico , 1 Jorge Luis Jimenez Macias , 2 Ishan Mohamed , 2 Saud Alhusaini , 3 Renee Read 2,4,5
  • 1. Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA
  • 2. Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia, USA
  • 3. Department of Neurology, Brown University, Providence, Rhode Island, USA
  • 4. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA
  • 5. Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA
*Correspondence to [email protected]
Disclosure:

Persico has received a scholarship from the American Academy of Neurology (AAN) for the AAN Annual Meeting 2026 (Future in Neurological Research Award); and is the Editorial Board Member of the AAN: Resident and Fellow Section. Mohamed has received a grant from the American Cancer Society (PF-25-1435269-01-PFCBI); and support for attending the ACS Research Conference from the American Cancer Society. Read has received support for the present manuscript via federal grant funding (R01NS126348) from NINDS, with payment to the institution; federal grant funding from NINDS (R21NS133633, R01NS132725, and R21NS116639), the Department of Defense (HT9425-24-1-0973 and HT94252310323), and the NCI (P30CA138292), with payment to the institution; support for attending meetings and/or travel from the American Brain Tumor Association and the Center for Scientific Review/National Institutes of Health; and equipment, materials, drugs, medical writing, gifts, or other services from Bausch Health for WINSHIP5070-20 (NCT04590664). The other authors have declared no conflicts of interest.

Citation:
Neurol AMJ. ;3[1]:44-45. https://doi.org/10.33590/neurolamj/EI91BI3R.
Keywords:
Glioma, Parkinson’s disease, LRRK2, survival, therapy.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

BACKGROUND AND AIMS

IDH-mutant Grade 4 astrocytomas are aggressive brain tumors with limited treatment options.1 According to the 2021 WHO central nervous system tumor classification, they are defined as diffuse high-grade gliomas characterized by IDH1/2, ATRX, and TP53 mutation, and sometimes CDKN2A/B deletion.2 This replaces the old nomenclature of “secondary glioblastomas” (GBM).2 Leucine-rich repeat kinase 2 (LRRK2) was first documented in a Japanese family with autosomal-dominant Parkinson’s disease.3 Park et al.4 demonstrated that LRRK2 is overexpressed in up to 40% of GBM specimens, with higher levels correlating with poor patient survival. LRRK2 is a cytoplasmic kinase that can activate the MAPK cascade, leading to uncontrolled cellular proliferation and resistance to apoptosis.5

MATERIALS AND METHODS

In silico analyses were performed using GlioVis, a web application for data visualization and analysis to explore brain tumor expression datasets.6 LRRK2 mRNA was examined in relation to overall survival and key high-grade glioma diagnostic and prognostic markers (CDKN2A/B, ATRX, PDGFRA, TERT, MGMT, TP53). Subgroup analyses were performed across transcriptional subtypes (classical, mesenchymal, and proneural).7 The proneural subtype is characterized by IDH1 and PDGFRA mutations, whereas the classical and mesenchymal subtypes are IDH– and PDGFRA-wild-type.7 GlioVis does not strictly follow the 2021 WHO classification of central nervous system tumors. As such, a GBM diagnosis in this

study refers to the GlioVis classification framework rather than the WHO 2021 criteria.

Figure 1: Kaplan–Meier survival curves for LRRK2 expression in female patients with GBM stratified by
proneural subtype.

RESULTS

In female patients with GBM, proneural subtype, low LRRK2 mRNA expression levels are associated with improved survival (hazard ratio: 0.23; p=0.017; (Figure 1). LRRK2 mRNA expression levels showed statistically significantly lower expression in the classical and mesenchymal subtypes compared to the proneural subtype (diff: 0.65, p=0.00; diff: 0.52, p=0.00) and statistically significantly higher LRRK2 expression levels in glioma-CpG island methylator phenotype (G-CIMP; diff: 0.77; p=0.00). LRRK2 mRNA expression levels revealed a correlation in the proneural subtype with CDKN2A (r=−0.37; p=0.04), ATRX (r=0.59; p=0.00), PDGFRA (r=0.26; p=0.03), TERT (r=−0.26; p=0.00), and MGMT (r=−0.49; p=0.01). No statistically significant correlations were identified with TP53  and CDKN2B.

DISCUSSION

Elevated LRRK2 mRNA expression, particularly in proneural GBM, is associated with worsened overall survival, which raises the question of LRRK2’s potential oncogenic role (Figure 1). LRRK2 mRNA expression levels appear more elevated in the proneural subtype of GBM, which is associated with IDH1 mutations.7 This evidence is solidified by the higher LRRK2 mRNA expression levels in G-CIMP, which are associated with an IDH-mutant genotype.8 In addition, a positive correlation with PDGFRA, whose higher mRNA expression levels are associated with IDH-mutant Grade 4 astrocytomas,9 and a negative correlation with CDKN2A, whose deletions are a diagnostic criterion for IDH-mutant Grade 4 astrocytomas,2 demonstrate that higher LRRK2 expression levels correlate with an IDH-mutant Grade 4 astrocytoma genotype. This is further supported by the negative correlation with TERT, whose higher expression levels are associated with TERT promoter mutation, which is atypical of IDH-mutant Grade 4 astrocytomas.10 LRRK2 has a negative correlation with MGMT in the proneural subtype. In IDH-mutant Grade 4 astrocytomas, MGMT promoter methylation is not prognostic or predictive of response to temozolomide.1 Hence, the clinical significance of the negative correlation between LRRK2 and MGMT mRNA expression levels in IDH-mutant Grade 4 astrocytomas remains unclear.

CONCLUSION

LRRK2 may represent a key oncogene in IDH-mutant Grade 4 astrocytomas. LRRK2 inhibition could represent a potential therapeutic strategy in these types of  high-grade gliomas.

References
Youssef G et al. Prognostic significance of O6-methylguanine-DNA methyltransferase promoter methylation status in isocitrate dehydrogenase-mutant glioma. Neuro Oncol. 2026;28(3):752-64. Louis DN et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol. 2021;23(8):1231-51. Funayama M et al. A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol. 2002;51(3):296-301. Park S et al. Suppression of glioblastoma stem cell potency and tumor growth via LRRK2 inhibition. Int J Stem Cells. 2024;17(3):319-29. Bahar ME et al. Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies. Signal Transduct Target Ther. 2023;8(1):455. Bowman RL et al. GlioVis data portal for visualization and analysis of brain tumor expression datasets. Neuro Oncol. 2017;19(1):139-41. Verhaak RG et al.; Cancer Genome Atlas Research Network. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98-110. Turcan S et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;483(7390):479-83. Rautajoki KJ et al. Genomic characterization of IDH-mutant astrocytoma progression to grade 4 in the treatment setting. Acta Neuropathol Commun. 2023;11(1):176. Jiang H et al. Unraveling the heterogeneity of WHO grade 4 gliomas: insights from clinical, imaging, and molecular characterization. Discov Oncol. 2025;16(1):111.

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