A Patient with Two Ewing's Sarcomas with Distinct EWS Fusion Transcripts
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《新英格兰医药杂志》
To the Editor: Members of the Ewing's family of tumors are characterized by rearrangements involving the EWS gene on chromosome 22q12 and fusion partners from the ETS oncogene family, most frequently FLI1 on chromosome 11q24 (frequency, 85 percent) or ERG on chromosome 21q22 (10 percent).1,2,3 So far, it is believed that one particular rearrangement is specific for any given Ewing's tumor and that no molecular shift occurs during progression. We describe a patient in whom two separate Ewing's tumors with distinct EWS translocations developed.
A 14-year-old girl without a family history of cancer was referred for the treatment of a CD99 (MIC2)–positive Ewing's sarcoma of the atlas, with extension into the left parapharyngeal space. A reverse-transcriptase polymerase chain reaction (RT-PCR) performed on RNA extracted from paraffin-embedded tissue led to the identification of a chimeric EWS/ERG fusion transcript characteristic of the t(21;22)(q22;q21) translocation (Figure 1A). Treatment consisting of surgery, radiotherapy, and polychemotherapy led to a complete remission that lasted for 56 months.
Figure 1. Molecular Heterogeneity in Specimens of Two Ewing's Tumors from a Single Patient.
Panel A shows a Ewing's sarcoma of the atlas (hematoxylin and eosin, x200); an EWS/ERG fusion transcript was detected (lanes 3 and 4), but an EWS/FLI1 fusion transcript was not (lanes 1 and 2). Panel B shows a Ewing's sarcoma of the humerus from the same patient (hematoxylin and eosin, x200); EWS/FLI1 was detected (lanes 5 and 6), but EWS/ERG was not (lanes 7 and 8).
Subsequently, on a routine bone scan, enhanced tracer uptake was detected in the right proximal humerus. Further imaging confirmed the presence of a bone tumor. A biopsy of the lesion was performed; like the lesion in the atlas, it was found to be a CD99-positive Ewing's sarcoma. To our surprise, RT-PCR of RNA extracted from unfixed tissue as well as from paraffin-embedded tissue and sequencing of the transcripts revealed an EWS/FLI1 type 5 translocation (Figure 1B). To rule out laboratory errors, molecular analysis of specimens of both tumors was repeated on stored tissue, and the presence of two distinct EWS fusion transcripts was confirmed. Microsatellite analysis confirmed that the specimens were indeed from the same patient.
We are not aware of previous reports of such molecular heterogeneity in specimens of Ewing's tumor from a single patient. Because Ewing's tumors are not associated with previous antineoplastic therapy or known cancer-susceptibility syndromes, a second primary Ewing's sarcoma may have developed by mere coincidence. Given the rarity of the disease, however, this explanation seems unlikely. Another, more intriguing hypothesis is that EWS translocations are not the first step in the evolution of Ewing's sarcomas, but rather are preceded by as-yet undefined predisposing molecular events not detected by contemporary cytogenetic analyses. Comparative molecular analyses of primary Ewing's sarcomas and their apparent metastatic osseous counterparts are warranted and may lead to further insights into the pathogenesis of this rare cancer.
Stefan S. Bielack, M.D., Ph.D.
Michael Paulussen, M.D., Ph.D.
University Children's Hospital
48129 Muenster, Germany
coss@uni-muenster.de
Gabriele K?hler, M.D., Ph.D.
University Hospital
48129 Muenster, Germany
References
Delattre O, Zucman J, Melot T, et al. The Ewing family of tumors -- a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 1994;331:294-299.
de Alava E, Gerald WL. Molecular biology of the Ewing's sarcoma/primitive neuroectodermal tumor family. J Clin Oncol 2000;18:204-213.
Kovar H. Ewing tumor biology: perspectives for innovative treatment approaches. Adv Exp Med Biol 2003;532:27-37.
A 14-year-old girl without a family history of cancer was referred for the treatment of a CD99 (MIC2)–positive Ewing's sarcoma of the atlas, with extension into the left parapharyngeal space. A reverse-transcriptase polymerase chain reaction (RT-PCR) performed on RNA extracted from paraffin-embedded tissue led to the identification of a chimeric EWS/ERG fusion transcript characteristic of the t(21;22)(q22;q21) translocation (Figure 1A). Treatment consisting of surgery, radiotherapy, and polychemotherapy led to a complete remission that lasted for 56 months.
Figure 1. Molecular Heterogeneity in Specimens of Two Ewing's Tumors from a Single Patient.
Panel A shows a Ewing's sarcoma of the atlas (hematoxylin and eosin, x200); an EWS/ERG fusion transcript was detected (lanes 3 and 4), but an EWS/FLI1 fusion transcript was not (lanes 1 and 2). Panel B shows a Ewing's sarcoma of the humerus from the same patient (hematoxylin and eosin, x200); EWS/FLI1 was detected (lanes 5 and 6), but EWS/ERG was not (lanes 7 and 8).
Subsequently, on a routine bone scan, enhanced tracer uptake was detected in the right proximal humerus. Further imaging confirmed the presence of a bone tumor. A biopsy of the lesion was performed; like the lesion in the atlas, it was found to be a CD99-positive Ewing's sarcoma. To our surprise, RT-PCR of RNA extracted from unfixed tissue as well as from paraffin-embedded tissue and sequencing of the transcripts revealed an EWS/FLI1 type 5 translocation (Figure 1B). To rule out laboratory errors, molecular analysis of specimens of both tumors was repeated on stored tissue, and the presence of two distinct EWS fusion transcripts was confirmed. Microsatellite analysis confirmed that the specimens were indeed from the same patient.
We are not aware of previous reports of such molecular heterogeneity in specimens of Ewing's tumor from a single patient. Because Ewing's tumors are not associated with previous antineoplastic therapy or known cancer-susceptibility syndromes, a second primary Ewing's sarcoma may have developed by mere coincidence. Given the rarity of the disease, however, this explanation seems unlikely. Another, more intriguing hypothesis is that EWS translocations are not the first step in the evolution of Ewing's sarcomas, but rather are preceded by as-yet undefined predisposing molecular events not detected by contemporary cytogenetic analyses. Comparative molecular analyses of primary Ewing's sarcomas and their apparent metastatic osseous counterparts are warranted and may lead to further insights into the pathogenesis of this rare cancer.
Stefan S. Bielack, M.D., Ph.D.
Michael Paulussen, M.D., Ph.D.
University Children's Hospital
48129 Muenster, Germany
coss@uni-muenster.de
Gabriele K?hler, M.D., Ph.D.
University Hospital
48129 Muenster, Germany
References
Delattre O, Zucman J, Melot T, et al. The Ewing family of tumors -- a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 1994;331:294-299.
de Alava E, Gerald WL. Molecular biology of the Ewing's sarcoma/primitive neuroectodermal tumor family. J Clin Oncol 2000;18:204-213.
Kovar H. Ewing tumor biology: perspectives for innovative treatment approaches. Adv Exp Med Biol 2003;532:27-37.