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Klotho Overexpression Is Frequently Associated With Upstream Rearrangements in Fusion-Negative Phosphaturic Mesenchymal Tumors of Bone and Sinonasal Tract.
Lee, Jen-Chieh; Hsieh, Tsung-Han; Kao, Yu-Chien; Tsai, Cheng-Fong; Huang, Hsuan-Ying; Shih, Ching-Yu; Song, Hsiang-Lin; Oda, Yoshinao; Chih-Hsueh Chen, Paul; Pan, Chin-Chen; Sittampalam, Kesavan; Petersson, Fredrik; Konishi, Eiichi; Chiu, Wei-Yih; Chen, Cheng-Fong; Carpenter, Thomas O; Lu, Tzu-Pin; Chang, Ching-Di; Huang, Shih-Chiang; Folpe, Andrew L.
Afiliação
  • Lee JC; Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: leejenchieh@ntuh.gov.tw.
  • Hsieh TH; Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan.
  • Kao YC; Department of Pathology, Taipei Medical University Hospital and School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • Tsai CF; Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
  • Huang HY; Department of Anatomical Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
  • Shih CY; Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University, Taipei, Taiwan.
  • Song HL; Department of Pathology, National Taiwan University Hospital Hsin-Chu Branch, Zhubei City, Taiwan.
  • Oda Y; Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • Chih-Hsueh Chen P; Department of Pathology, National Yang Ming University and Taipei Veterans General Hospital, Taipei, Taiwan.
  • Pan CC; Department of Pathology, National Yang Ming University and Taipei Veterans General Hospital, Taipei, Taiwan.
  • Sittampalam K; Division of Pathology, Singapore General Hospital, Singapore, Singapore.
  • Petersson F; Department of Pathology, National University Health System, Singapore, Singapore.
  • Konishi E; Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
  • Chiu WY; Division of Metabolism and Endocrinology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
  • Chen CF; Department of Orthopedics, Taipei Veterans General Hospital, Taipei, Taiwan.
  • Carpenter TO; Department of Pediatrics (Endocrinology), Yale University School of Medicine, New Haven, Connecticut.
  • Lu TP; Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University, Taipei, Taiwan.
  • Chang CD; Department of Radiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
  • Huang SC; Department of Anatomic Pathology, Linkou Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
  • Folpe AL; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
Mod Pathol ; 36(12): 100336, 2023 Dec.
Article em En | MEDLINE | ID: mdl-37742927
ABSTRACT
Phosphaturic mesenchymal tumors (PMT) are uncommon neoplasms that cause hypophosphatemia/osteomalacia mainly by secreting fibroblast growth factor 23. We previously identified FN1FGFR1/FGF1 fusions in nearly half of the PMTs and frequent KL (Klotho or α-Klotho) overexpression in only those with no known fusion. Here, we studied a larger cohort of PMTs for KL expression and alterations. By FN1 break-apart fluorescence in situ hybridization (FISH) and reappraisal of previous RNA sequencing data, 6 tumors previously considered "fusion-negative" (defined by negative results of FISH for FN1FGFR1 fusion and FGF1 break-apart and/or of RNA sequencing) were reclassified as fusion-positive PMTs, including 1 containing a novel FN1ZACN fusion. The final cohort of fusion-negative PMTs included 33 tumors from 32 patients, which occurred in the bone (n = 18), soft tissue (n = 10), sinonasal tract (n = 4), and brain (n = 1). In combination with previous work, RNA sequencing, RNA in situ hybridization, and immunohistochemistry showed largely concordant results and demonstrated KL/α-Klotho overexpression in 17 of the 28 fusion-negative and none of the 10 fusion-positive PMTs studied. Prompted by a patient in this cohort harboring germline KL upstream translocation with systemic α-Klotho overexpression and multifocal PMTs, FISH was performed and revealed KL rearrangement in 16 of the 33 fusion-negative PMTs (one also with amplification), including 14 of the 17 cases with KL/α-Klotho overexpression and none of the 11 KL/α-Klotho-low fusion-negative and 11 fusion-positive cases studied. Whole genomic sequencing confirmed translocation and inversion in 2 FISH-positive cases involving the KL upstream region, warranting further investigation into the mechanism whereby these rearrangements may lead to KL upregulation. Methylated DNA immunoprecipitation and sequencing suggested no major role of promoter methylation in KL regulation in PMT. Interestingly, KL-high/-rearranged cases seemed to form a clinicopathologically homogeneous group, showing a predilection for skeletal/sinonasal locations and typically matrix-poor, cellular solitary fibrous tumor-like morphology. Importantly, FGFR1 signaling pathways were upregulated in fusion-negative PMTs regardless of the KL status compared with non-PMT mesenchymal tumors by gene set enrichment analysis, perhaps justifying FGFR1 inhibition in treating this subset of PMTs.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Seios Paranasais / Neoplasias de Tecidos Moles / Mesenquimoma Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Seios Paranasais / Neoplasias de Tecidos Moles / Mesenquimoma Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article