Biological Role and Clinical Implications of MYOD1(L122R) Mutation in Rhabdomyosarcoma

SIMPLE SUMMARY: The myogenic differentiation 1 gene (MYOD1) p.L122R mutation was first discovered in a subset of clinically aggressive rhabdomyosarcomas in both adults and children. It occurs most frequently in spindle cell (Sp) or sclerosing (Sc) RMS, but also occasionally in ERMS, including 3% of all PAX fusion-negative RMS. The presence of the MYOD1(L122R) mutation seems to be associated with a very poor prognosis, especially when it occurs concomitantly with other mutations such as PIK3CA. In this review, we consider the known biological effects of MYOD1 mutations and present a review of published cases of RMS with MYOD1 mutations. Together, the reviewed biological characteristics and the clinical features focus attention on this specific subgroup of patients with poor outcome and highlight the need to identify an optimal therapeutic strategy. 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.