Alveolar rhabdomyosarcoma (ARMS) is an aggressive soft tissue tumor of the striated muscle lineage that occurs in children and young adults. This cancer is associated with 2;13 and 1;13 chromosomal translocations that juxtapose the PAX3 and PAX7 loci with the FKHR locus to create chimeric genes encoding PAX3-FKHR or PAX7-FKHR fusion products. To detect these fusions in tumor specimens, polymerase chain reaction, in situ hybridization, and Southern blot strategies have been developed. Using these assays, Intergroup Rhabdomyosarcoma Study Group (IRSG) pilot studies provided evidence to indicate that these gene fusions are specific markers for ARMS diagnosis, that the PAX3-FKHR and PAX&-FKHR subtypes are associated with differing outcomes in ARMS patients, and that high sensitivity assays are capable of detecting clinically significant submicroscopic metastatic disease. In addition, recent studies suggest the existence of additional fusion subtypes in ARMS cases that do not detectably express the typical PAX3-FKHR or PAX7-FKHR fusion transcripts. The preliminary studies support the hypotheses that fusion gene detection will play a significant role in the diagnosis, monitoring, and management of ARMS patients. To further explore this hypothesis in the setting of a large multi-institutional clinical trial with uniformly treated and diagnosed patients and centrally collected clinical specimens and clinical data, the IRSG Biology Committee will study the relationship of fusion subtype to clinical outcome, other patient characteristics, histopathologic features, and other biological parameters in the patients prospectively entered on the IRS-V study. Gene fusion subtype of the primary tumor will be compared with clinical data to determine the predictive value of these genetic markers in ARMS management. Fusion negative ARMS tumors will be investigated for variant and cryptic gene fusions to establish additional fusion categories for consideration in these clinical correlative studies. Bone marrow and peripheral blood specimens from these patients will also be assayed to determine the predictive value of submicroscopic disease detection in metastatic sites. Finally, biological markers of proliferation and apoptosis status will be examined to determine their relationship with fusion subtype and other parameters in these patients. These studies will provide a definitive analysis of the occurrence and clinical significance of these genetic alterations in ARMS, and will ultimately impact on the future design of clinical protocols for the treatment of ARMS patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CONC (01))
Program Officer
Wu, Roy S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Medicine
United States
Zip Code
Sumegi, Janos; Streblow, Renae; Frayer, Robert W et al. (2010) Recurrent t(2;2) and t(2;8) translocations in rhabdomyosarcoma without the canonical PAX-FOXO1 fuse PAX3 to members of the nuclear receptor transcriptional coactivator family. Genes Chromosomes Cancer 49:224-36
Bridge, Julia A (2008) Contribution of cytogenetics to the management of poorly differentiated sarcomas. Ultrastruct Pathol 32:63-71
Mercado, Gabriela E; Barr, Frederic G (2007) Fusions involving PAX and FOX genes in the molecular pathogenesis of alveolar rhabdomyosarcoma: recent advances. Curr Mol Med 7:47-61
Kapels, Kayla M; Nishio, Jun; Zhou, Ming et al. (2007) Embryonal rhabdomyosarcoma with a der(16)t(1;16) translocation. Cancer Genet Cytogenet 174:68-73
Parham, David M; Qualman, Stephen J; Teot, Lisa et al. (2007) Correlation between histology and PAX/FKHR fusion status in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group. Am J Surg Pathol 31:895-901
Lae, M; Ahn, E H; Mercado, G E et al. (2007) Global gene expression profiling of PAX-FKHR fusion-positive alveolar and PAX-FKHR fusion-negative embryonal rhabdomyosarcomas. J Pathol 212:143-51
Xia, Shujuan J; Rajput, Prerna; Strzelecki, Donna M et al. (2007) Analysis of genetic events that modulate the oncogenic and growth suppressive activities of the PAX3-FKHR fusion oncoprotein. Lab Invest 87:318-25
Barr, Frederic G; Smith, Lynette M; Lynch, James C et al. (2006) Examination of gene fusion status in archival samples of alveolar rhabdomyosarcoma entered on the Intergroup Rhabdomyosarcoma Study-III trial: a report from the Children's Oncology Group. J Mol Diagn 8:202-8
Barr, Frederic G; Zhang, Paul J (2006) The impact of genetics on sarcoma diagnosis: an evolving science. Clin Cancer Res 12:5256-7
Nishio, Jun; Althof, Pamela A; Bailey, Jacqueline M et al. (2006) Use of a novel FISH assay on paraffin-embedded tissues as an adjunct to diagnosis of alveolar rhabdomyosarcoma. Lab Invest 86:547-56

Showing the most recent 10 out of 21 publications