Biological Role and Clinical Implications of MYOD1L122R Mutation in Rhabdomyosarcoma

Abstract

Major progress in recent decades has furthered our clinical and biological understanding of rhabdomyosarcoma (RMS) with improved stratification for treatment based on risk factors. Clinical risk factors alone were used to stratify patients for treatment in the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS 2005 protocol. The current EpSSG overarching study for children and adults with frontline and relapsed rhabdomyosarcoma (FaR-RMS NCT04625907) includes FOXO1 fusion gene status in place of histology as a risk factor. Additional molecular features of significance have recently been recognized, including the MYOD1^L122R gene mutation. Here, we review biological information showing that MYOD1^L122R blocks cell differentiation and has a MYC-like activity that enhances tumorigenesis and is linked to an aggressive cellular phenotype. MYOD1^L122R mutations can be found together with mutations in other genes, such as PIK3CA, as potentially cooperating events. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, ten publications in the clinical literature involving 72 cases were reviewed. MYOD1^L122R mutation in RMS can occur in both adults and children and is frequent in sclerosing/spindle cell histology, although it is also significantly reported in a subset of embryonal RMS. MYOD1^L122R mutated tumors most frequently arise in the head and neck and extremities and are associated with poor outcome, raising the issue of how to use MYOD1^L122R in risk stratification and how to treat these patients most effectively.

Keywords: MYOD1; children; high-risk; sclerosing rhabdomyosarcoma; spindle cell.

Figure 1

How MYOD1^L122R can contribute towards an aggressive phenotype in RMS. MYOD1^L122R contributes to aggressive disease in RMS, leading to poor outcomes, in two potential ways. Firstly, MYOD1^L122R can act in a dominant negative manner and bind MYOD1-responsive promoters, blocking normal MYOD1 from binding but failing to transactivate these myogenic genes, resulting in a failure of myoblasts to differentiate and keeping them in a proliferating state. Secondly, MYOD1^L122R can additionally bind to MYC-responsive genes and activate an oncogenic program of transcription.