Fusion power.

Top Line: What molecular alterations drive different subtypes of rhabdomyosarcoma?

The Study: We’ve seen in many childhood malignancies that molecular categorization has important prognostic and predictive implications. Rhabdomyosarcoma, the most common soft tissue sarcoma in children, has been broadly categorized as embryonal or alveolar histology and then further subdivided upon clinicopathologic features. More recently, the presence or absence of FOXO1 fusion has been used for molecular risk stratification. Alveolar RMS is typically FOXO1 fusion positive (FP) whereas embryonal RMS is often fusion negative (FN) and driven by more diverse molecular alterations. Here is a genomic analysis of a large cohort of 614 patients treated on prospective, international cooperative group trials that attempts to shed light on the molecular landscape of RMS. Tumors were first categorized as FOXO1 fusion+ (FP) or fusion- (FN). Among FP tumors, the most common mutations involved CDK4 (13%) and MYCN (10%). FN tumors most commonly had mutations involving RAS isoforms (>50% total). However, 21% had no driver mutation at all. Instead, many of these tumors are driven by numerous genetic and chromosomal alterations. When it came to survival, TP53 mutation was predictive of worse outcome for both FP and FN tumors. In addition, MYOD1 mutation was also associated with poor outcomes among FN tumors.

TBL: An improved understanding of the molecular alterations that drive different subtypes of RMS will help develop future therapies and treatment paradigms for this diverse disease. | Shern, J Clin Oncol 2021

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