Tumor-induced osteomalacia (TIO) is a rare disorder caused by a phosphaturic mesenchymal tumor (PMT) secreting fibroblast growth factor 23 (FGF23). The aim of this study was to analyze PMTs for their Show more
Tumor-induced osteomalacia (TIO) is a rare disorder caused by a phosphaturic mesenchymal tumor (PMT) secreting fibroblast growth factor 23 (FGF23). The aim of this study was to analyze PMTs for their transcriptomic characteristics. We performed single-cell RNA (n = 3) alongside bulk RNA sequencing of PMTs (n = 5) and surrounding bone tissue (n = 4) obtained during tumor removal in 10 patients (age 44 (41;64), serum phosphate (Pi)- 0.54 (0.43; 0.59) mM/L, FGF23-113 (40; 205) pg/ml). We revealed a total of 22,449 cells divided into 13 different categories. We identified the heterogeneity of the PMT cell cluster and subsequently divided it into two tumor clusters 1 and 2 characterized by the deeper epithelial-mesenchymal phenotype transition, higher FGF23 expression as well as various SNP and CNV. We further identified tumor cell differentiation driving regulons ERG and EGR3, based on scoring by allele expression and velocity based pseudotime on a trajectory that may play a critical role in the tumorigenesis of PMTs. In both single-cell and bulk transcriptome analysis we found upregulation of vesicle-specific and exocytosis associated genes (SLC30A3, SYT1, STX1A and SNAP25) which most likely represent molecular mechanisms of active secretion in all PMT samples. We report transmembrane protein coding genes expressed in all PMTs specifically in tumor cell clusters (PHEX, ERBB4, PCDH7, LRRFIP2) which are suggested as potential diagnostic targets. We confirmed the presence of FN1-FGFR1 fusion genes and Klotho expression in most PMTs (6 out of 8). Conclusion: specific SNARE proteins gene upregulation along with transcriptional signatures of PMT offer new insights into its pathogenesis which may be further studied for diagnostic and therapeutic interventions. Show less
This study is aimed at investigating the clinical and genetic characteristics of 244 unrelated probands diagnosed with multiple osteochondromas (MO). The diagnosis of MO typically involves identifying Show more
This study is aimed at investigating the clinical and genetic characteristics of 244 unrelated probands diagnosed with multiple osteochondromas (MO). The diagnosis of MO typically involves identifying multiple benign bone tumors known as osteochondromas (OCs) through imaging studies and physical examinations. However, cases with both OCs and enchondromas (ECs) may indicate the more rare condition metachondromatosis (MC), which is assumed to be distinct disease. Previous cohort studies of MO found heterozygous loss-of-function (LoF) variants only in the Show less