Somatic mutations in SQSTM1 detected in affected tissues from patients with sporadic paget's disease of bone

Anand Merchant, Magda Smielewska, Nimit Patel, Jennifer D. Akunowicz, Elizabeth A. Saria, John D. Delaney, Robin J. Leach, Margaret Seton, Marc F. Hansen

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


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 Sequestosomel 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 C1215Tmutations 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 C1215Tmutation, 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 under-standing of this disease.

Original languageEnglish (US)
Pages (from-to)484-494
Number of pages11
JournalJournal of Bone and Mineral Research
Issue number3
StatePublished - Mar 2009


  • Laser capture microdissection
  • Paget's disease of bone
  • Pagetic osteosarcoma
  • Sequestosome 1
  • Somatic mutations

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine


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