RAS pathway mutations have been linked to relapse and chemotherapy resistance in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, comprehensive data on the frequency and prognostic value of subclonal mutations in well-defined subgroups using highly sensitive and quantitative methods are lacking. Targeted deep sequencing of 13 RAS pathway genes was performed in 461 pediatric BCP-ALL cases at initial diagnosis and in 19 diagnosis-relapse pairs. Mutations were present in 44.2% of patients, with 24.1% carrying a clonal mutation. Mutation frequencies were highest in high hyperdiploid, infant t(4;11)-rearranged, BCR-ABL1-like and B-other cases (50-70%), whereas mutations were less frequent in ETV6-RUNX1-rearranged, and rare in TCF3-PBX1- and BCR-ABL1-rearranged cases (27-4%). RAS pathway-mutated cells were more resistant to prednisolone and vincristine ex vivo. Clonal, but not subclonal, mutations were linked to unfavorable outcome in standard- and high-risk-treated patients. At relapse, most RAS pathway mutations were clonal (9 of 10). RAS mutant cells were sensitive to the MEK inhibitor trametinib ex vivo, and trametinib sensitized resistant cells to prednisolone. We conclude that RAS pathway mutations are frequent, and that clonal, but not subclonal, mutations are associated with unfavorable risk parameters in newly diagnosed pediatric BCP-ALL. These mutations may designate patients eligible for MEK inhibitor treatment.

中文翻译：

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RAS通路突变作为小儿B细胞前体急性淋巴细胞白血病治疗适应性的预测性生物标志物。

RAS通路突变与小儿B细胞前体急性淋巴细胞白血病（BCP-ALL）的复发和化疗耐药性相关。但是，缺乏使用高度灵敏和定量方法确定的亚组中亚克隆突变的频率和预后价值的综合数据。在461例小儿BCP-ALL病例中，在19例诊断-复发对中，对13种RAS途径基因进行了靶向深度测序。44.2％的患者存在突变，其中24.1％的患者患有克隆突变。在高双倍体，婴儿t（4; 11）重排，BCR-ABL1样和B其他情况下，突变频率最高（50-70％），而在ETV6-RUNX1重排中，突变频率较低，在ETV6-RUNX1重排中很少TCF3-PBX1和BCR-ABL1重新排列的病例（27-4％）。RAS途径突变的细胞离体对泼尼松龙和长春新碱的耐药性更高。在标准和高风险治疗的患者中，克隆突变而非亚克隆突变与不良预后相关。在复发时，大多数RAS途径突变是克隆性的（10个中的9个）。RAS突变细胞离体对MEK抑制剂曲美替尼敏感，而曲美替尼使耐药细胞对泼尼松龙敏感。我们得出的结论是，RAS通路突变很常见，而克隆（而非亚克隆）突变与新诊断的儿科BCP-ALL的不利风险参数有关。这些突变可以指定适合MEK抑制剂治疗的患者。大多数RAS途径突变都是克隆性的（10个中的9个）。RAS突变细胞离体对MEK抑制剂曲美替尼敏感，而曲美替尼使耐药细胞对泼尼松龙敏感。我们得出的结论是，RAS通路突变很常见，而克隆（而非亚克隆）突变与新诊断的儿科BCP-ALL的不利风险参数有关。这些突变可以指定适合MEK抑制剂治疗的患者。大多数RAS途径突变都是克隆性的（10个中的9个）。RAS突变细胞离体对MEK抑制剂曲美替尼敏感，而曲美替尼使耐药细胞对泼尼松龙敏感。我们得出的结论是，RAS通路突变很常见，而克隆（而非亚克隆）突变与新诊断的儿科BCP-ALL的不良风险参数有关。这些突变可以指定适合MEK抑制剂治疗的患者。