ZNF687 Mutations in an Extended Cohort of Neoplastic Transformations in Paget's Disease of Bone: Implications for Clinical Pathology.

Neoplastic transformation is a rare but serious complication of Paget's disease of bone (PDB), occurring in fewer than 1% of individuals with polyostotic disease. Their prognosis is poor, with less than 50% surviving 5 years. In 2016, the genetic alteration of giant cell tumor (GCT) complicating PDB was identified as a founder germline mutation (P937R) in the ZNF687 gene. However, the study population was exclusively of Italian descent, and patients of different ethnic origins were not studied. To fill this gap, herein we performed mutation analysis of ZNF687 in a GCT in the pelvis of a 45-year-old black American woman with polyostotic PDB. The P937R mutation in ZNF687 was found in her tumor but, as expected, the ancestral haplotype that characterizes the Italian GCT/PDB patients was not found. Furthermore, we identified two additional Italian GCT/PDB patients with this ZNF687 mutation, now constituting a cohort of 18 GCT/PDB cases, all harboring the identical mutation. We also searched for ZNF687 mutations in a unique collection of tumor tissues derived from Italian PDB patients, including 28 osteosarcomas (OS/PDB), 8 undifferentiated sarcomas (SRC/PDB), 1 fibrosarcoma (FS/PDB), and 1 chondrosarcoma (CS/PDB). We identified the P937R mutation in one SRC/PDB and a different ZNF687 mutation (R331W) in 1 of 28 pagetic osteosarcomas. Thus, whereas GCT/PDB pathogenesis globally seems to involve the P937R mutation in ZNF687, other neoplasms associated with PDB seem to be less related to mutations in this gene. Finally, we identified the G34W mutation in the H3F3A gene in the maxillary tumor masses of two PDB patients, defining them as conventional GCT rather than GCT/PDB. Thus, combined molecular analysis of H3F3A and ZNF687 is essential to clarify the origin and diagnosis of tumors in PDB. © 2020 American Society for Bone and Mineral Research.

Serum Antibodies Against Simian Virus 40 Large T Antigen, the Viral Oncoprotein, in Osteosarcoma Patients.

Human osteosarcoma (OS) is a rare human cancer, mostly occurring in children and adolescents. Simian virus 40 (SV40 = Macaca mulatta polyomavirus 1) sequences have been detected in different human cancers, including osteosarcoma. SV40 is an oncogenic virus in vivo, whereas it transforms different kinds of mammalian cells, as well as distinct human cell types. SV40 injected in rodents induces tumors of different histotypes, such as bone and brain tumors. Herein, the association between OS and SV40 large T antigen (Tag) was studied by employing indirect ELISAs using synthetic peptides that mimic different epitopes of the SV40 Tag, the viral oncoprotein. Indirect ELISAs were used to detect serum IgG antibodies against this oncogenic virus in samples from OS patients. Controls were sera from healthy subjects (HS) and oncological patients affect by breast cancer (BC), which is not associated with SV40. It turned out that sera of OS patients had a higher prevalence of SV40 Tag antibodies, 35%, compared to HS, 20% and BC, 19%, respectively. The different prevalence of SV40 Tag antibodies revealed in OS vs. HS and vs. BC is statistically significant with P < 0.05 and P < 0.01, respectively. Our immunological data indicate a significantly higher prevalence of antibodies against SV40 Tag epitopes in serum samples from OS patients compared to HS and BC, the controls. These results suggest an association between OS and SV40 Tag, indicating that this oncogenic virus may be a cofactor in OS development.

Elevated TNFR1 and serotonin in bone metastasis are correlated with poor survival following bone metastasis diagnosis for both carcinoma and sarcoma primary tumors.

PURPOSE: There is an urgent need for therapies that will reduce the mortality of patients with bone metastasis. In this study, we profiled the protein signal pathway networks of the human bone metastasis microenvironment. The goal was to identify sets of interacting proteins that correlate with survival time following the first diagnosis of bone metastasis. EXPERIMENTAL DESIGN: Using Reverse Phase Protein Microarray technology, we measured the expression of 88 end points in the bone microenvironment of 159 bone metastasis tissue samples derived from patients with primary carcinomas and sarcomas. RESULTS: Metastases originating from different primary tumors showed similar levels of cell signaling across tissue types for the majority of proteins analyzed, suggesting that the bone microenvironment strongly influences the metastatic tumor signaling profiles. In a training set (72 samples), TNF receptor 1, alone (P = 0.0013) or combined with serotonin (P = 0.0004), TNFα (P = 0.0214), and RANK (P = 0.0226), was associated with poor survival, regardless of the primary tumor of origin. Results were confirmed by (i) analysis of an independent validation set (71 samples) and (ii) independent bioinformatic analysis using a support vector machine learning model. Spearman rho analysis revealed a highly significant number of interactions intersecting with ERα S118, serotonin, TNFα, RANKL, and matrix metalloproteinase in the bone metastasis signaling network, regardless of the primary tumor. The interaction network pattern was significantly different in the short versus long survivors. CONCLUSIONS: TNF receptor 1 and neuroendocrine-regulated protein signal pathways seem to play an important role in bone metastasis and may constitute a novel drug-targetable mechanism of seed-soil cross talk in bone metastasis.