FGFR1 Mutation and Massive Chromosome Loss Drive Malignant Transformation of Low-Grade Gliomas

Yanming Chen¹Ruze Tang²Dong Wan^3,4Yongjun Xiang⁵Si Chen^3,4Huafei Chen^3,4Xiaoxiao Dai⁶Rong Rong⁷Sheng Xiao^3,4Qing Lan^1*Shungen Huang^2*Hangzhou Wang^5*

• ¹Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China, Suzhou, China
• ²Department of General Surgery, Children's Hospital of Soochow University, Suzhou, China, Suzhou, China
• ³Advanced Molecular Pathology Institute of Soochow University and SANO, Suzhou, China, Suzhou, China
• ⁴Suzhou SANO Precision Medicine Ltd, SANO Medical Laboratories, Suzhou, China, Suzhou, China
• ⁵Department of Neurosurgery, Children's Hospital of Soochow University, Suzhou, China, Suzhou, China
• ⁶Department of Pathology, The Second Affiliated Hospital of Soochow University, Suzhou, China, Suzhou, China
• ⁷Department of Biological Sciences, Xi An Jiaotong-Liverpool University, Suzhou 215000, China, Suzhou, China

The mitogen-activated protein kinase (MAPK) signaling pathway plays roles in cell proliferation, differentiation, and apoptosis, all crucial for cellular transformation. It's no surprise that MAPK alterations are prevalent in numerous tumors. Several critical genes in the MAPK signaling pathway, including BRAF, FGFR, and NF1, are mutated in brain tumors. For example, FGFR1 mutation or rearrangement has been described in pilocytic astrocytoma, diffuse astrocytoma, and dysembryoplastic neuroepithelial tumor (DNT). These MAPK-activated brain tumors are benign and seldom progress to malignancies, with the mechanisms driving this rare transformation not yet fully understood. In this study, we present two cases of high-grade glioma characterized by a single activating mutation of FGFR1 and massive chromosome loss (near-haploid genome). Similar haploidy is found in 3 additional high-grade astrocytoma by literature review, all harbor a single gene mutation in the MAPK pathway. We propose that the massive chromosome loss might serve as a significant mechanism contributing to the unusual malignant transformation of benign brain tumors activated by the MAPK pathway.