Mutations of MAP2K1 are frequent in pediatric-type follicular lymphoma and result in ERK pathway activation
Mutations of MAP2K1 are frequent in pediatric-type follicular lymphoma and result in ERK pathway activation
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DOI：
10.1182/blood-2017-03-776278
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发表时间：
2017-07-20
期刊：
影响因子：
20.3
通讯作者：
Quintanilla-Martinez, Leticia
中科院分区：
文献类型：
--
作者：
Schmidt, Janine;Enric Ramis-Zaldivar, Joan;Quintanilla-Martinez, Leticia
儿童型滤泡性淋巴瘤（PTFL）是一种具有独特临床病理特征的 B 细胞淋巴瘤。最近，已经描述了对其发病机制具有潜在重要性的反复遗传改变，这些改变破坏了与生发中心反应（TNFRSF14、IRF8）、免疫逃逸（TNFRSF14）和抗凋亡（MAP2K1）相关的通路。为了更深入地了解 PTFL 的发病机制，我们对 43 个病例进行了综合分析，这些病例先前已通过靶向下一代测序和拷贝数阵列进行了表征。 49% (20/41) 的病例中发现了 MAP2K1 突变，其频率仅次于 TNFRSF14 突变 (22/41; 54%)，并且所有这些突变都存在于 81% 的病例中。对 MAP2K1 下游靶细胞外信号调节激酶的免疫组织化学分析表明，在可评估的病例中其磷酸化，并与 MAP2K1 突变的等位基因频率具有良好的相关性。 15%（6/39）的病例存在IRF8p.K66R突变，4例伴有TNFRSF14突变。这个热点似乎是 PTFL 的特色。总之，TNFRSF14 和 MAP2K1 突变是 PTFL 中最常见的基因改变，并且在大多数情况下独立发生，表明这两种突变可能在 PTFL 淋巴瘤发生中发挥重要作用。
Pediatric-type follicular lymphoma (PTFL) is a B-cell lymphoma with distinctive clinicopathological features. Recently, recurrent genetic alterations of potential importance for its pathogenesis that disrupt pathways associated with the germinal center reaction (TNFRSF14, IRF8), immune escape (TNFRSF14), and anti-apoptosis (MAP2K1) have been described. In an attempt to shed more light onto the pathogenesis of PTFL, an integrative analysis of these mutations was undertaken in a large cohort of 43 cases previously characterized by targeted next-generation sequencing and copy number array. Mutations in MAP2K1 were found in 49% (20/41) of the cases, second in frequency to TNFRSF14 alterations (22/41; 54%), and all together were present in 81% of the cases. Immunohistochemical analysis of the MAP2K1 downstream target extracellular signal-regulated kinase demonstrated its phosphorylation in the evaluable cases and revealed a good correlation with the allelic frequency of the MAP2K1 mutation. The IRF8p.K66R mutation was present in 15%(6/39) of the cases and was concomitant with TNFRSF14 mutations in 4 cases. This hot spot seems to be highly characteristic for PTFL. In conclusion, TNFRSF14 and MAP2K1 mutations are the most frequent genetic alterations found in PTFL and occur independently inmost cases, suggesting that both mutations might play an important role in PTFL lymphomagenesis.