Rhabdomyosarcoma, Embryonal, 1
A number sign (#) is used with this entry because of evidence that rhabdomyosarcoma can be caused by somatic mutation in the SLC22A18 gene (602631) on chromosome 11p15.
MappingScrable et al. (1987) generalized the hypothesis of somatic chromosomal interchanges at mitosis as the basis of retinoblastoma (180200). To the study of other tumors, the proposed model suggests that predisposing recessive mutations are revealed by exchanges that result in homozygous (or hemizygous) defect at the tumor locus. This would suggest that for tumors with no known cytogenetic aberrations, one could find the location of these genes by delineating the smallest overlapping region of genetic homozygosity shared among tumors of the same type. They applied this rationale to rhabdomyosarcoma, a 'pediatric tumor.'
Koufos et al. (1985) had suggested that a locus on chromosome 11 was involved in rhabdomyosarcoma. By the use of multiple markers on chromosome 11 in 4 tumors (comparing the tumor DNA with constitutional DNA in each case), Scrable et al. (1987) mapped the rhabdomyosarcoma locus to 11pter-p15.5. They suggested that the clinical association of rhabdomyosarcoma with the Beckwith-Wiedemann syndrome (130650) may have its basis in involvement at this locus; likewise, this locus may be involved in those cases of the WAGR syndrome (194070) in which rhabdomyosarcoma occurs.
Stenman and Sager (1987) reviewed extensive prior data from chromosome studies of tumorigenic and tumor-derived Chinese hamster cells suggesting the presence of a tumor-suppressor gene on hamster 3p. They showed that 6 genes on human 11p (INS, CAT, HBBC, CALC, PTH, and HRAS) can be localized by in situ hybridization to Chinese hamster chromosome 3. INS and CAT were located close to the centromere on 3p, whereas HBBC, CALC, and PTH were at 3q3-q4 and HRAS at 3q4. Two tumor-suppressor genes have been described on 11p: one that determines Wilms tumor, which is linked to CAT (115500), and one that determines rhabdomyosarcoma, which is linked to INS (176730). Stenman and Sager (1987) suggested that the Chinese hamster-suppressor gene may be closely linked to INS or CAT in that species. The striking histologic resemblance of rhabdomyosarcoma to fetal striated muscle extends to the genes they express. MYOD1 (159970) is one of these. Scrable et al. (1990) demonstrated an evolutionarily conserved muscle-specific linkage group comprising MYOD1 and LDHA (150000), which is located close to the RMSCR locus.
InheritanceScrable et al. (1989) examined the role of genome imprinting in the development of embryonal rhabdomyosarcoma. Imprinting is an epigenetic, gamete-of-origin-dependent, allele-inactivation process. Pursuing the observation that these tumors arise from cells that are clonally isodisomic for loci on chromosome 11p, they demonstrated that the isodisomic chromosome 11p alleles were always of paternal origin in both familial and sporadic cases. If a tumor-suppressor allele was subject either to mutation or to epigenetic inactivation by passage through the male germline, then any cell that contained such an allele would be functionally hemizygous at the affected locus. Thus, in either a genetically or an epigenetically caused hemizygote, only 1 additional event would be required to produce a null phenotype. In the classic Knudson model, tumor-suppressor alleles that carry alterations in nucleotide sequence will be inherited as the predisposing mutation. In such families, the disease will be genetically linked to markers on the chromosome that carries the tumor-suppressor allele, and the sex of the parent from whom the defective allele is inherited is not predicted to have an effect. This appears to be the case for families with retinoblastoma (180200), adenomatous polyposis coli (175100), and bilateral acoustic neuroma (101000). In a second class of familial tumors, an epigenetically inactivated tumor-suppressor allele will be inherited as the predisposing mutation. Because the inactivation of this allele need not be dependent on the allele itself but will reflect the activity of the gene or genes involved in generating or maintaining the genome imprint, the inheritance of the tumor phenotype will not be linked to the tumor-suppressor locus.
PathogenesisThe findings of Pedone et al. (1994) suggest that acquisition of a double dosage of the gene for insulinlike growth factor-2 (IGF2; 147470) may be an important step before the initiation or progression of rhabdomyosarcoma. The IGF2 gene is imprinted, the maternally derived allele being inactive in normal tissues. Pedone et al. (1994) found that whereas monoallelic expression of IGF2 was conserved in normal adult muscle tissue, 2 or more copies of active IGF2 alleles, arising by either relaxation of imprinting or duplication of the active allele, were found in 9 out of 11 (82%) rhabdomyosarcomas retaining heterozygosity at 11p15, regardless of the histologic subtype. The findings did not extend to leiomyosarcomas; they detected only 1 case of partial reactivation of the maternal IGF2 allele out of 7 tumors of that subtype tested.
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. Hgf/Sf-transgenic, Ink4a/Arf-deficient mice succumbed to multifocal, highly invasive rhabdomyosarcoma tumors by about 4 months of age. 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. Yu et al. (2004) established highly and poorly metastatic rhabdomyosarcoma cell lines from these animals. They used cDNA microarray analysis to identify a set of genes whose expression was significantly different between highly and poorly metastatic cells. Subsequent in vivo functional studies showed that ezrin, encoded by Vil2 (123900), and Six1 (601205) have essential roles in determining the metastatic fate of rhabdomyosarcoma cells. Yu et al. (2004) found that VIL2 and SIX1 expression was enhanced in human rhabdomyosarcoma tissue, significantly correlating with clinical stage.
Molecular GeneticsIn a rhabdomyosarcoma cell line, Schwienbacher et al. (1998) found a G-to-A transition at nucleotide 688 that introduced an arginine in place of a cysteine in the product of the BWR1A gene (SLC22A18; 602631.0002). The change was present in homozygous state, suggesting that loss of the normal allele occurred during tumorigenesis.
HistoryLoh et al. (1992) showed that the transfer of a normal human chromosome 11 into an embryonal rhabdomyosarcoma cell line resulted in a dramatic loss of the proliferative capacity of the cells. Cells that possessed only the long arm of chromosome 11 also demonstrated a decreased growth rate. Their functional data supported molecular studies indicating loss of genetic information on 11p15 during the development of embryonal rhabdomyosarcoma. In addition, however, their studies demonstrated the existence of a second gene on the long arm of chromosome 11, previously unrecognized by molecular analyses, which negatively regulates the growth of embryonal rhabdomyosarcoma cell lines.