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MAP Kinase Signaling Pathway in Pediatric Rhabdomyosarcomas

Background: Rhabdomyosarcoma (RMS) is the most common malignant mesenchymal tumor in children and adolescents. Overall survival of patients with newly diagnoses RMS is 75% but drops to 25% after relapse. Alteration of the MAPK (Mitogen-activated proteins kinase) signaling pathway have an important role in the genesis and progression of various adult's tumors. A thorough study of these pathways in RMS could therefore guide toward potential new molecular targets and pave the way for new therapeutic approaches.

Methods: Retrospective descriptive multicenter study of 111 patients with RMS treated between 2005 and 2023 with available somatic molecular analysis. An analyze on the main classic MAPK pathway genes: FGFR 1-2-3-4; RAS genes: HRAS, NRAS, KRAS; RAF and BRAF; MEK and ERK in RNA sequencing, was performed.

Results: Overall, 46 cases (41%) were identified with at least a MAPK pathway gene mutation. These included 23 cases (21%) with at least one FGFR mutation, 20 cases (18%) with any types of RAS mutations, six cases (5%) with RAF mutations and five cases (4%) with MEK-ERK mutations (multiple possible). Most of them occurred in Fusion Negative RMS (FNRMS; 37/77, 48%), were also present in MYOD1 RMS (5/9; 58 %), are seldom in Fusion Positive RMS (4/25, 16%). No difference in overall or event-free survivals, between cases with or without at least one alteration in the MAPK pathway, was documented.

Conclusions: Therefore, 30 cases (27%) of RMS cases could present a targetable MAPK pathway with already available drugs. Testing these MAPK inhibitors in phase I/II clinical trials is expected to enhance progress towards improved treatment assignment, management and outcomes for patients with MAPK altered RMS.