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Variation of mutant allele frequency in NRAS Q61 mutated melanomas
Zofia Hélias-Rodzewicz1,2, Elisa Funck-Brentano3,4, Nathalie Terrones3
1Research Unit EA4340 Biomarkers in Cancerology and Hemato Oncology, Versailles SQY University, Paris-Saclay University, 9, Avenue Charles de Gaulle, 92104, Boulogne-Billancourt, France. zofia.helias-ext@aphp.fr.
Background:
Somatic mutations of BRAF or NRAS activating the MAP kinase cell signaling pathway are present in 70% of cutaneous melanomas. The mutant allele frequency of BRAF V600E (M%BRAF) was recently shown to be highly heterogeneous in melanomas. The present study focuses on the NRAS Q61 mutant allele frequency (M%NRAS).
Methods:
Retrospective quantitative analyze of 104 NRAS mutated melanomas was performed using pyrosequencing. Mechanisms of M%NRAS imbalance were studied by fluorescence in situ hybridization (FISH) and microsatellite analysis.
Results:
M%NRAS was increased in 27.9% of cases. FISH revealed that chromosome 1 instability was the predominant mechanism of M%NRAS increase, with chromosome 1 polysomy observed in 28.6% of cases and intra-tumor cellular heterogeneity with copy number variations of chromosome 1/NRAS in 23.8%. Acquired copy-neutral loss of heterozygosity (LOH) was less frequent (19%). However, most samples with high M%NRAS had only one copy of NRAS locus surrounding regions suggesting a WT allele loss. Clinical characteristics and survival of patients with either <60% or ≥60% of M%NRAS were not different.
Conclusion:
As recently shown for M%BRAF, M%NRAS is highly heterogeneous. The clinical impacts of high M%NRAS should be investigated in a larger series of patients.
Insights
NRAS Q61 mutant allele frequency (M%NRAS) is highly heterogeneous in cutaneous melanomas, similar to BRAF V600E. Chromosome 1 instability, particularly polysomy, is a key driver of M%NRAS imbalance, but clinical impact remains unclear.
Area of Science:
- Oncology
- Cancer Genomics
- Molecular Biology
Background:
- Somatic mutations in BRAF or NRAS activate the MAP kinase pathway in 70% of cutaneous melanomas.
- BRAF V600E mutant allele frequency (M%BRAF) exhibits significant heterogeneity.
- This study investigates the NRAS Q61 mutant allele frequency (M%NRAS) heterogeneity.
Purpose of the Study:
- To quantify M%NRAS in NRAS-mutated melanomas.
- To identify mechanisms underlying M%NRAS imbalance.
- To explore potential clinical correlations of M%NRAS levels.
Main Methods:
- Retrospective analysis of 104 NRAS-mutated melanomas.
- Quantitative pyrosequencing for M%NRAS determination.
- Fluorescence in situ hybridization (FISH) and microsatellite analysis to study imbalance mechanisms.
Main Results:
- M%NRAS was increased in 27.9% of cases.
- Chromosome 1 instability (polysomy, copy number variations) was the predominant mechanism for increased M%NRAS.
- Loss of heterozygosity was less frequent; high M%NRAS often associated with WT allele loss.
- No significant difference in clinical characteristics or survival based on M%NRAS levels (<60% vs. ≥60%).
Conclusions:
- M%NRAS, like M%BRAF, demonstrates significant heterogeneity in cutaneous melanoma.
- Chromosome 1 instability is a primary driver of M%NRAS variation.
- Further investigation in larger patient cohorts is needed to clarify the clinical significance of high M%NRAS.
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