Molecular Pathogenesis of Rhabdomyosarcoma

Abstract

© 2 0 0 2 L a n d e s B i o s c i e n c e . N o t f o r d i s t r i b u t i o n .[Cancer Biology & ABSTRACTRhabdomyosarcoma (RMS) is a family of soft tissue tumors that are associated with the skeletal muscle lineage and generally occur in the pediatric population. Based on histopathologic features, two subtypes, embryonal (ERMS) and alveolar (ARMS), were identified and associated with distinct clinical characteristics and genetic alterations. ARMS is associated with 2;13 or 1;13 chromosomal translocations, which generate PAX3-FKHR and PAX7-FKHR fusion products, respectively. These translocations result in altered expression, function, and subcellular localization of the fusion products relative to the wild-type proteins, and ultimately contribute to oncogenic behavior by modifying growth, differentiation, and apoptosis pathways. In contrast to the specific translocations found in ARMS, most ERMS cases have allelic loss at chromosome 11p15.5. Chromosome fragment transfer studies demonstrated that this region represses tumor cell growth, suggesting the presence of tumor suppressor gene(s) in this region. In both ERMS and ARMS, there is evidence of collaborating alterations that affect common targets, such as the p53 and RB pathways. One mechanism for perturbing these pathways involves amplification of genes such as MDM2 and CDK4; these amplification events occur frequently in ARMS but only rarely in ERMS. Therefore, despite similarities in the downstream targets of these genetic alterations, the striking cytogenetic and molecular differences between ARMS and ERMS indicate distinct molecular etiologies in these two subtypes.

Altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma

“…Xia et al showed that MDM2 amplification events occur frequently in alveolar type, but only rarely in embryonal type. 27 In our study, of the three cases with MDM2 amplification, one case was alveolar type while two were embryonal type. MDM2 showed no association with the patients' prognoses or with any of the other clinicopathologic parameters, including histological type and age.…”

FOXOs, cancer and regulation of apoptosis

“…These fusions alter the transactivation properties of the respective proteins and are thereby thought to contribute to carcinogenesis. The main evidence supporting this notion is that the Pax3-FOXO1 fusion protein is a more potent transcription activator than normal Pax3 protein in increasing the transcription of Pax3 target gene (Xia et al, 2002). The fusion protein is able to induce oncogenic transformation in cell culture (Scheidler et al, 1996;Kempf and Vogt, 1999;Xia and Barr, 2004), suggesting that the fusion protein may function as an oncogenic transcription factor by enhancing activation of normal PAX3 target genes.…”

Rhabdomyosarcoma: Current Challenges and Their Implications for Developing Therapies

“…The Banbury White Papers published in CSH Perspectives were devised as a framework for distilling these conclusions and disseminating them to the wider research community. distinct DNA methylation patterns, and extremely low sequence variation rates, as opposed to loss of heterozygosity at the 11p15.5 locus, frequent chromosomal gains, and a prominent role for RAS pathway activation in fusion-negative tumors (Xia et al 2002;Langenau et al 2007;Hettmer et al 2011;Chen et al 2013;Schneider et al 2014;Shern et al 2014).…”

“…Risk of treatment failure in pediatric RMS is stratified based on primary site, histology, and extent of disease. These stratification parameters do not currently include genotypic differences between fusion-positive and fusion-negative RMS or the full range of clinical, histological, and molecular variability seen across the RMS spectrum (Parham 2001;Xia et al 2002;Missiaglia et al 2012;Skapek et al 2013). …”