IRSG STUDIES OF ALVEOLAR RHABDOMYOSARCOMA GENE FUSIONS

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DESCRIPTION: 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.