PMID- 37742927 OWN - NLM STAT- MEDLINE DCOM- 20231225 LR - 20231225 IS - 1530-0285 (Electronic) IS - 0893-3952 (Linking) VI - 36 IP - 12 DP - 2023 Dec TI - Klotho Overexpression Is Frequently Associated With Upstream Rearrangements in Fusion-Negative Phosphaturic Mesenchymal Tumors of Bone and Sinonasal Tract. PG - 100336 LID - S0893-3952(23)00241-7 [pii] LID - 10.1016/j.modpat.2023.100336 [doi] AB - Phosphaturic mesenchymal tumors (PMT) are uncommon neoplasms that cause hypophosphatemia/osteomalacia mainly by secreting fibroblast growth factor 23. We previously identified FN1::FGFR1/FGF1 fusions in nearly half of the PMTs and frequent KL (Klotho or alpha-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 FN1::FGFR1 fusion and FGF1 break-apart and/or of RNA sequencing) were reclassified as fusion-positive PMTs, including 1 containing a novel FN1::ZACN 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/alpha-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 alpha-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/alpha-Klotho overexpression and none of the 11 KL/alpha-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. CI - Copyright (c) 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved. FAU - Lee, Jen-Chieh AU - Lee JC AD - Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: leejenchieh@ntuh.gov.tw. FAU - Hsieh, Tsung-Han AU - Hsieh TH AD - Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan. FAU - Kao, Yu-Chien AU - Kao YC AD - 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. FAU - Tsai, Cheng-Fong AU - Tsai CF AD - Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. FAU - Huang, Hsuan-Ying AU - Huang HY AD - Department of Anatomical Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. FAU - Shih, Ching-Yu AU - Shih CY AD - Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University, Taipei, Taiwan. FAU - Song, Hsiang-Lin AU - Song HL AD - Department of Pathology, National Taiwan University Hospital Hsin-Chu Branch, Zhubei City, Taiwan. FAU - Oda, Yoshinao AU - Oda Y AD - Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Chih-Hsueh Chen, Paul AU - Chih-Hsueh Chen P AD - Department of Pathology, National Yang Ming University and Taipei Veterans General Hospital, Taipei, Taiwan. FAU - Pan, Chin-Chen AU - Pan CC AD - Department of Pathology, National Yang Ming University and Taipei Veterans General Hospital, Taipei, Taiwan. FAU - Sittampalam, Kesavan AU - Sittampalam K AD - Division of Pathology, Singapore General Hospital, Singapore, Singapore. FAU - Petersson, Fredrik AU - Petersson F AD - Department of Pathology, National University Health System, Singapore, Singapore. FAU - Konishi, Eiichi AU - Konishi E AD - Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan. FAU - Chiu, Wei-Yih AU - Chiu WY AD - Division of Metabolism and Endocrinology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. FAU - Chen, Cheng-Fong AU - Chen CF AD - Department of Orthopedics, Taipei Veterans General Hospital, Taipei, Taiwan. FAU - Carpenter, Thomas O AU - Carpenter TO AD - Department of Pediatrics (Endocrinology), Yale University School of Medicine, New Haven, Connecticut. FAU - Lu, Tzu-Pin AU - Lu TP AD - Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University, Taipei, Taiwan. FAU - Chang, Ching-Di AU - Chang CD AD - Department of Radiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. FAU - Huang, Shih-Chiang AU - Huang SC AD - 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. FAU - Folpe, Andrew L AU - Folpe AL AD - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. LA - eng PT - Journal Article DEP - 20230922 PL - United States TA - Mod Pathol JT - Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc JID - 8806605 RN - 104781-85-3 (Fibroblast Growth Factor 1) SB - IM MH - Humans MH - In Situ Hybridization, Fluorescence MH - Fibroblast Growth Factor 1/genetics MH - *Soft Tissue Neoplasms/genetics MH - *Mesenchymoma/genetics/pathology MH - Translocation, Genetic MH - *Paranasal Sinuses/pathology OTO - NOTNLM OT - RNA sequencing OT - epigenetics OT - phosphaturic mesenchymal tumor OT - tumorigenesis OT - whole genomic sequencing OT - alpha-Klotho EDAT- 2023/09/25 00:42 MHDA- 2023/12/25 06:43 CRDT- 2023/09/24 19:17 PHST- 2023/07/16 00:00 [received] PHST- 2023/08/31 00:00 [revised] PHST- 2023/09/15 00:00 [accepted] PHST- 2023/12/25 06:43 [medline] PHST- 2023/09/25 00:42 [pubmed] PHST- 2023/09/24 19:17 [entrez] AID - S0893-3952(23)00241-7 [pii] AID - 10.1016/j.modpat.2023.100336 [doi] PST - ppublish SO - Mod Pathol. 2023 Dec;36(12):100336. doi: 10.1016/j.modpat.2023.100336. Epub 2023 Sep 22.