Correspondence

Osteosarcoma Derived from Donor Stem Cells Carrying the Norrie's Disease Gene

N Engl J Med 2008; 359:2502-2504December 4, 2008

Article

To the Editor:

There have been few reports of osteosarcoma after allogeneic bone marrow transplantation.1 We report the development of osteosarcoma in a recipient 17 years after stem-cell transplantation.

A 23-month-old boy with β-thalassemia received a bone marrow transplant from his HLA-identical 11-year-old brother in September 1989. Norrie's disease had been diagnosed in the donor at 12 months of age, after enucleation of the right eye was performed because a bilateral retinoblastoma was suspected. No genetic analysis was conducted at the time of surgery. Norrie's disease is an X-linked recessive disease caused by mutations in the NDP gene on Xp11.4.2 It primarily affects the eye and almost always leads to blindness. The chemotherapy regimen before the bone marrow transplantation consisted of high-dose cyclophosphamide and busulfan. From day 30, the recipient was a complete hematopoietic chimera. Seventeen years later, a metastatic chondroblastic osteosarcoma of the pelvis developed in the 18-year-old recipient. Despite aggressive treatment, the patient died of tumor progression 22 months after the diagnosis of osteosarcoma and 19 years after stem-cell transplantation.

An osteosarcoma cell line that was established from the recipient's tumor had a doubling time of 168 hours (7 days) (the normal doubling time in a generated osteosarcoma cell line is 1.4 to 37.0 days). The cells expressed mesenchymal stem-cell markers (CD44, CD29, CD105, CD90, and CD73) at a very high level (Figure 1Figure 1Osteosarcoma Cell-Line Immunophenotype and Chimerism.), but they did not express CD45, CD14, CD34, CD49, or CD24. Cells from the osteosarcoma cell line were examined by means of cytogenetic analysis and fluorescence in situ hybridization (FISH) with the use of a specific probe for the p53 gene.3 Fifty metaphases were analyzed after GTG banding. Two distinct karyotypes were found: 47XY,−5,+22,+m and 45XY,−12,−15,+m. Blood samples from the recipient and donor had wild-type copies of chromosome 17, whereas the osteosarcoma cell line showed trisomy 17 in 22 of 100 interphase nuclei. Neither the cytogenetic analysis nor p53 FISH analysis of the primary tumor was performed because of an inadequate specimen, and for ethical reasons, donor mesenchymal stem cells were not analyzed at the time of the diagnosis of osteosarcoma. A semiquantitative method based on polymerase-chain-reaction amplification of polymorphic genes showed complete donor chimerism of recipient hematopoietic cells, the cells from the osteosarcoma-biopsy specimen, and the osteosarcoma cell line (Figure 1).3 Moreover, the blood samples from the donor and the recipient, the osteosarcoma-biopsy specimen, and the osteosarcoma cell line had a mutation of L15R of exon 2 of the NDP gene, whereas swab cells from the recipient's oral cavity did not.

Our data suggest the donor origin of the osteosarcoma. The mutated NDP in the osteosarcoma cells was most likely a marker of chimerism, because cancer did not develop in the donor, and Norrie's disease is not associated with an increased risk of cancer.

Massimo Berger, M.D.
Michela Muraro, M.D.
Franca Fagioli, M.D.
Ospedale Infantile Regina Margherita, 10126 Turin, Italy
massimo.berger@unito.it

Stefano Ferrari, M.D.
Istituto Ortopedico Rizzoli, 40136 Bologna, Italy

3 References

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Citing Articles (3)

Citing Articles

1. 1

   Idriss M Bennani-Baiti. (2011) Epigenetic and epigenomic mechanisms shape sarcoma and other mesenchymal tumor pathogenesis. Epigenomics 3:6, 715-732
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2. 2

   Alexander B. Mohseny, Pancras C. W. Hogendoorn. (2011) Concise Review: Mesenchymal Tumors: When Stem Cells Go Mad. STEM CELLS 29:3, 397-403
   CrossRef

3. 3

   Alexander B Mohseny, Karoly Szuhai, Salvatore Romeo, Emilie P Buddingh, Inge Briaire-de Bruijn, Daniëlle de Jong, Melissa van Pel, Anne-Marie Cleton-Jansen, Pancras CW Hogendoorn. (2009) Osteosarcoma originates from mesenchymal stem cells in consequence of aneuploidization and genomic loss of Cdkn2. The Journal of Pathology 219:3, 294-305
   CrossRef