TY - JOUR
T1 - ZNF687 Mutations in an Extended Cohort of Neoplastic Transformations in Paget's Disease of Bone
T2 - Implications for Clinical Pathology
AU - Scotto di Carlo, Federica
AU - Pazzaglia, Laura
AU - Mumm, Steven
AU - Benassi, Maria S.
AU - De Chiara, Annarosaria
AU - Franchi, Alessandro
AU - Parafioriti, Antonina
AU - Righi, Alberto
AU - Esposito, Teresa
AU - Whyte, Michael P.
AU - Gianfrancesco, Fernando
N1 - Funding Information:
We are grateful to Deborah J Veis, MD, PhD, at Washington University School of Medicine, for making it possible for us to perform DNA analysis on tumor tissue of our American patient. This work was supported by the Italian Association for Cancer Research (AIRC) (IG-2014 no. 15707 to FG), by the Progetti di Rilevante Interesse Nazionale (PRIN) (2015F3JHMB to FG), by POR Campania FESR 2014/2020 (Project SATIN to FG), and Shriners Hospitals for Children (to SM and MPW). Authors' roles: FG conceived the idea, supervised all aspects of the work, and takes responsibility for the integrity of the data analysis. FG and FSdC designed the experiments. FSdC conducted the experiments. LP, SM, MSB, ADC, AF, AP, and AR collected materials. FSdC drafted the manuscript. FG and MPW revised the manuscript. All authors read and approved the final manuscript.
Publisher Copyright:
© 2020 American Society for Bone and Mineral Research
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
KW - NEOPLASTIC TRANSFORMATION
KW - PAGET's DISEASE OF BONE
KW - ZNF687 MUTATION
UR - http://www.scopus.com/inward/record.url?scp=85081377726&partnerID=8YFLogxK
U2 - 10.1002/jbmr.3993
DO - 10.1002/jbmr.3993
M3 - Article
C2 - 32106343
AN - SCOPUS:85081377726
SN - 0884-0431
VL - 35
SP - 1974
EP - 1980
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
IS - 10
ER -