Hélias-Rodzewicz Zofia, Funck-Brentano Elisa, Terrones Nathalie, Beauchet Alain, Zimmermann Ute, Marin Cristi, Saiag Philippe, Emile Jean-François
Research Unit EA4340 Biomarkers in Cancerology and Hemato Oncology, Versailles SQY University, Paris-Saclay University, 9, Avenue Charles de Gaulle, 92104, Boulogne-Billancourt, France.
Department of Pathology, Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, France.
BMC Dermatol. 2017 Jul 1;17(1):9. doi: 10.1186/s12895-017-0061-x.
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).
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.
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.
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.
激活丝裂原活化蛋白激酶（MAP）细胞信号通路的BRAF或NRAS体细胞突变存在于70%的皮肤黑色素瘤中。BRAF V600E（M%BRAF）的突变等位基因频率最近在黑色素瘤中显示出高度异质性。本研究聚焦于NRAS Q61突变等位基因频率（M%NRAS）。
采用焦磷酸测序对104例NRAS突变的黑色素瘤进行回顾性定量分析。通过荧光原位杂交（FISH）和微卫星分析研究M%NRAS失衡的机制。
27.9%的病例中M%NRAS升高。FISH显示1号染色体不稳定是M%NRAS升高的主要机制，28.6%的病例观察到1号染色体多体性，23.8%的病例存在肿瘤内细胞异质性伴1号染色体/NRAS拷贝数变异。获得性拷贝中性杂合性缺失（LOH）较少见（19%）。然而，大多数M%NRAS高的样本仅具有NRAS基因座周围区域的一个拷贝，提示野生型等位基因缺失。M%NRAS<60%或≥60%的患者的临床特征和生存率无差异。
正如最近M%BRAF所显示的那样，M%NRAS高度异质性。高M%NRAS的临床影响应在更大系列的患者中进行研究。
