Somatic mutations in SQSTM1 detected in affected tissues from patients with sporadic Paget's disease of bone.
Paget's disease of bone (PDB) is a focal disorder of bone remodeling that leads to overgrowth of affected bone, with rare progression to osteosarcoma. Extensive studies of familial PDB showed that a majority of cases harbor germline mutations in the Sequestosome1 gene (SQSTM1). In contrast, little is known about the mutational status of SQSTM1 in sporadic PDB. We hypothesized that somatic SQSTM1 mutations might occur in the affected tissues of sporadic PDB and pagetic osteosarcoma. We used laser capture microdissection to capture homogeneous populations of cells from the affected bone or tumor of patients with sporadic PDB or pagetic osteosarcoma, respectively. DNA from these samples and appropriate controls was used for sequence analysis and allelic discrimination analysis. Two of five patients with sporadic PDB had SQSTM1(C1215T) mutations detected in their affected bone but not in their blood samples, indicating a somatic origin of the mutations. Samples from three of five sporadic pagetic osteosarcoma patients had the SQSTM1(C1215T) mutation, whereas the normal adjacent tissue from two of these tumors clearly lacked the mutation, again indicating an occurrence of somatic events. No SQSTM1 mutations were found in primary adolescent osteosarcomas. The discovery of somatic SQSTM1 mutations in sporadic PDB and pagetic osteosarcoma shows a role for SQSTM1 in both sporadic and inherited PDB. The discovery of somatically acquired mutations in both the diseased bone and tumor samples suggests a paradigm shift in our understanding of this disease.
Merchant
Anand
A
Center for Molecular Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
Smielewska
Magda
M
Patel
Nimit
N
Akunowicz
Jennifer D
JD
Saria
Elizabeth A
EA
Delaney
John D
JD
Leach
Robin J
RJ
Seton
Margaret
M
Hansen
Marc F
MF
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000483:Alleles; D001483:Base Sequence; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D042282:Microdissection; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010001:Osteitis Deformans / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000473:pathology; D012516:Osteosarcoma / Q000150:complications / Q000235:genetics / Q000473:pathology; D000071456:Sequestosome-1 Protein; D014764:Viral Proteins
D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D014764:Viral Proteins