Rhabdomyosarcoma 2

A number sign (#) is used with this entry because of evidence that alveolar rhabdomyosarcoma results from fusion of the PAX3 gene (606597) on chromosome 2 with the FKHR gene (FOXO1A; 136533) on chromosome 13 as a result of a translocation t(2;13), or from fusion of the PAX7 gene (167410) on chromosome 1 with the FKHR gene as a result of a translocation t(1;13).

Douglass et al. (1987) found a specific translocation, t(2;13)(q35;q14), in 5 cases of advanced rhabdomyosarcoma. It was identified directly in cells that had metastasized from bone marrow in 1 patient, and in xenografts derived from the tumors of 4 other patients. Wang-Wuu et al. (1988) did chromosomal analysis of 16 rhabdomyosarcomas (4 primary tumors and 12 tumors after nude mouse passage). Of 7 alveolar tumors, 4 had t(2;13)(q37;q14); in 2 of these it was the only structural abnormality. Eight of 9 embryonal tumors had trisomy 2.

In a rhabdomyosarcoma of the eyelid present at birth, Hayashi et al. (1988) found a translocation t(2;8)(q37;q13). They considered that the region 2q37 may be important in the development of this neoplasm. The tumor had features of embryonal rhabdomyosarcoma with no features typical of alveolar structures. Thus, there appeared to be 2 loci involved in rhabdomyosarcoma: one on chromosome 11 (see 268210) and one on chromosome 2.

By a physical mapping strategy, Barr et al. (1991) delimited the rhabdomyosarcoma t(2;13) breakpoint to a narrow region of chromosome 13. Shapiro et al. (1992) demonstrated that the FLT oncogene (165070), previously localized to 13q12 by in situ hybridization, is located proximal to the chromosome 13 breakpoint and is not a target for disruption by the tumor specific translocation t(2;13). Shapiro et al. (1992) and Barr et al. (1992) gave the breakpoint in chromosome 2 as q35 and the breakpoint in chromosome 13 as q14. Barr et al. (1992) compared the location of the breakpoint on chromosome 2 with the breakpoints in other cell lines and, by a comparison with the linkage map of the syntenic region on mouse chromosome 1, concluded that the t(2;13) breakpoint is probably most closely flanked by loci INHA (147380) and ALPI (171740).

Barr et al. (1993) determined that PAX3 (606597), which had previously been found to be mutated in Waardenburg syndrome, was affected by a t(2;13)(q35;q14) translocation associated with alveolar rhabdomyosarcoma. The rearrangement breakpoints occurred within an intron downstream of the paired box and homeodomain-encoding regions. Upstream PAX3 sequences hybridized to a novel transcript in t(2;13)-containing lines. Galili et al. (1993) demonstrated that the chromosome 13 gene that is fused with PAX3 is a member of the 'forkhead' domain family (FKHR).

Bennicelli et al. (1996) studied the mechanism for transcriptional gain of function resulting from a PAX3-FKHR fusion.

Among primary rhabdomyosarcoma tumors, Anderson et al. (2001) found that 37 had t(2;13)/PAX3-FKHR, 8 had t(1;13) PAX7-FKHR, and 46 had neither translocation. One or the other of the characteristic translocations was found in 31 of 38 (82%) of alveolar cases. Univariate survival analysis showed the presence of the translocation t(2;13)/PAX3-FKHR to be an adverse prognostic factor. The authors suggested that with the difficulties in morphologic diagnosis of alveolar rhabdomyosarcoma on small needle biopsy specimens, the molecular data may be useful in treatment stratification.

Sharp et al. (2002) showed that simultaneous loss of Ink4a/Arf (600160) function and disruption of Met (164860) signaling in Ink4a/Arf -/- mice transgenic for hepatocyte growth factor/scatter factor (Hgf/Sf; 142409) induces rhabdomyosarcoma with extremely high penetrance and short latency. In cultured myoblasts, Met activation and Ink4a/Arf loss suppressed myogenesis in an additive fashion. Sharp et al. (2002) concluded that human MET and INK4A/ARF, situated at the nexus of pathways regulating myogenic growth and differentiation, represent critical targets in rhabdomyosarcoma pathogenesis. The marked synergism in mice between aberrant MET signaling and INK4A/ARF inactivation, lesions individually implicated in human rhabdomyosarcoma, suggested a therapeutic combination to combat this devastating childhood cancer.