HRAS – Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma, comprising embryonal (ERMS) and alveolar (ARMS) subtypes. Somatic activating mutations in RAS family oncogenes are frequent events in RMS pathogenesis, with HRAS (HGNC:5173) variants observed across multiple cohorts. The predominant mutational hotspot in HRAS is codon 61, resulting in impaired GTP hydrolysis and constitutive signalling.

In a cohort of 98 ERMS cases, 5 (5%) harbored HRAS mutations at codons 12, 14, or 61, including HRAS p.Gln61Arg (PMID:34755412). A separate report described HRAS p.Gln61Arg in a rhabdomyosarcoma arising within a giant congenital melanocytic nevus (PMID:39912655). In Chinese ARMS specimens, HRAS mutations were identified in 3 of 8 cases (37.5%) alongside PIK3CA alterations (PMID:24641407).

These somatic HRAS variants are exclusively missense changes at well-known oncogenic hotspots, with all reported cases showing p.Gln61Arg. No familial segregation data are available for these somatic events. The recurrent nature of HRAS hotspot mutations across independent RMS cohorts supports a moderate level of genetic evidence.

Functional crystallography studies of H-ras p21 mutants, including Gln61His and Arg12Val, revealed disrupted nucleotide binding and hydrolysis, explaining the gain-of-function phenotype of oncogenic HRAS substitutions (PMID:2199064). These structural insights align with the tumour-driving role of HRAS mutations in RMS.

Overall, the association between somatic HRAS mutations and RMS is supported by moderate genetic evidence (9 unrelated tumours with recurrent p.Gln61Arg) and limited functional evidence. Additional studies could further clarify prognostic and therapeutic implications.

Key Take-home: HRAS hotspot mutations, particularly p.Gln61Arg, define a molecular subset of RMS amenable to targeted RAS pathway inhibition.

References

• Genes, Chromosomes & Cancer • 2022 • Clinicopathologic and survival correlates of embryonal rhabdomyosarcoma driven by RAS/RAF mutations. PMID:34755412
• The American Journal of Dermatopathology • 2025 • Rhabdomyosarcoma Harboring NRAS or HRAS Mutation Arising in Giant Congenital Melanocytic Nevus: Report of 2 Cases. PMID:39912655
• Asian Pacific Journal of Cancer Prevention : APJCP • 2014 • Compound HRAS/PIK3CA mutations in Chinese patients with alveolar rhabdomyosarcomas. PMID:24641407
• Cell • 1990 • Three-dimensional structures of H-ras p21 mutants: molecular basis for their inability to function as signal switch molecules. PMID:2199064

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