RNA Sequencing Reveals Novel Oncogenic Fusions and Depicts Detailed Fusion Transcripts of FN1-FGFR1 in Phosphaturic Mesenchymal Tumors

Xiaoding Liu; Xianglin Yin; Dongmei Li; Kaimi Li; Hui Zhang; Junliang Lu; Liangrui Zhou; Jie Gao; Jing Wang; Huanwen Wu; Zhiyong Liang

doi:10.1016/j.modpat.2023.100266

RNA Sequencing Reveals Novel Oncogenic Fusions and Depicts Detailed Fusion Transcripts of FN1-FGFR1 in Phosphaturic Mesenchymal Tumors

Mod Pathol. 2023 Oct;36(10):100266. doi: 10.1016/j.modpat.2023.100266. Epub 2023 Jun 28.

Authors

Affiliations

¹ Department of Pathology, State Key Laboratory of Complex Severe and Rare Disease, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Department of Pathology, State Key Laboratory of Complex Severe and Rare Disease, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: wuhuanwen10700@pumch.cn.
³ Department of Pathology, State Key Laboratory of Complex Severe and Rare Disease, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: liangzy@pumch.cn.

PMID: 37391169
DOI: 10.1016/j.modpat.2023.100266

Abstract

Phosphaturic mesenchymal tumors (PMTs) are rare neoplasms of soft tissue or bone. Although previous studies revealed that approximately 50% of PMTs harbor FN1::FGFR1 fusions, the molecular mechanisms in the remaining cases are largely unknown. In this study, fusion genes were investigated using RNA-based next-generation sequencing in 76 retrospectively collected PMTs. Novel fusions were validated with Sanger sequencing and fluorescence in situ hybridization. Fusion genes were detected in 52/76 (68.4%) PMTs, and 43/76 (56.6%) harbored FN1::FGFR1 fusions. Fusion transcripts and breakpoints of the FN1::FGFR1 fusions were diverse. The most common fusion transcript was between exon 20 of FN1 and exon 9 of FGFR1 (7/43, 16.3%). The most upstream breakpoint of the FN1 gene was located at the 3' end of exon 12, and the most downstream breakpoint of the FGFR1 gene was at the 5' end of exon 9, suggesting the inessential nature of the third fibronectin-type domain of FN1 and the necessity of the transmembrane domain of FGFR1 in the FN1::FGFR1 fusion protein, respectively. Moreover, the reciprocal FGFR1::FN1 fusions, which had not been identified in previous studies, were detected in 18.6% (8/43) of FN1::FGFR1 fusion-positive PMTs. Novel fusions were identified in 6/76 (7.9%) FN1::FGFR1 fusion-negative PMTs, including 2 involving FGFR: FGFR1::USP33 (1/76, 1.3%) and FGFR1::TLN1 (1/76, 1.3%). Other novel fusions identified were the PDGFRA::USP35 (1/76, 1.3%), SPTBN1::YWHAQ (1/76, 1.3%), GTF2I::RALGPS1 (1/76, 1.3%), and LTBP1::VWA8 (1/76, 1.3%) fusions. In addition to these novel fusions, FN1::FGFR2 (1/76, 1.3%), NIPBL::BEND2 (1/76, 1.3%), and KIAA1549::BRAF fusions (1/76, 1.3%) were also identified in FN1::FGFR1-negative cases arising from the thigh, ilium, and acetabulum, respectively. The frequency of oncogenic fusions was significantly higher (P = .012) in tumors derived from extremities (29/35, 82.9%) compared with other locations (23/41, 56.1%). No significant correlation was identified between fusions and recurrence (P = .786). In conclusion, we report fusion transcripts and breakpoints of FN1::FGFR1 in PMTs in detail, providing insights into fusion protein functions. We also revealed that a considerable proportion of PMTs without FN1::FGFR1 fusion carried novel fusions, providing further insight into the genetic basis of PMTs.

Keywords: gene fusion; high-throughput nucleotide sequencing; phosphaturic mesenchymal tumor; soft tissue neoplasms; tumor-induced osteomalacia.