Ozawa Michael G, Bhaduri Aparna, Chisholm Karen M, Baker Steven A, Ma Lisa, Zehnder James L, Luna-Fineman Sandra, Link Michael P, Merker Jason D, Arber Daniel A, Ohgami Robert S
Department of Pathology, Stanford University, Stanford, CA, USA.
Program in Epithelial Biology, Stanford University, Stanford, CA, USA.
Mod Pathol. 2016 Oct;29(10):1212-20. doi: 10.1038/modpathol.2016.102. Epub 2016 Jun 24.
Pediatric-type follicular lymphoma and pediatric marginal zone lymphoma are two of the rarest B-cell lymphomas. These lymphomas occur predominantly in the pediatric population and show features distinct from their more common counterparts in adults: adult-type follicular lymphoma and adult-type nodal marginal zone lymphoma. Here we report a detailed whole-exome deep sequencing analysis of a cohort of pediatric-type follicular lymphomas and pediatric marginal zone lymphomas. This analysis revealed a recurrent somatic variant encoding p.Lys66Arg in the transcription factor interferon regulatory factor 8 (IRF8) in 3 of 6 cases (50%) of pediatric-type follicular lymphoma. This specific point mutation was not detected in pediatric marginal zone lymphoma or in adult-type follicular lymphoma. Additional somatic point mutations in pediatric-type follicular lymphoma were observed in genes involved in transcription, intracellular signaling, and cell proliferation. In pediatric marginal zone lymphoma, no recurrent mutation was identified; however, somatic point mutations were observed in genes involved in cellular adhesion, cytokine regulatory elements, and cellular proliferation. A somatic variant in AMOTL1, a recurrently mutated gene in splenic marginal zone lymphoma, was also identified in a case of pediatric marginal zone lymphoma. The overall non-synonymous mutational burden was low in both pediatric-type follicular lymphoma and pediatric marginal zone lymphoma (4.6 mutations per exome). Altogether, these findings support a distinctive genetic basis for pediatric-type follicular lymphoma and pediatric marginal zone lymphoma when compared with adult subtypes and to one another. Moreover, identification of a recurrent point mutation in IRF8 provides insight into a potential driver mutation in the pathogenesis of pediatric-type follicular lymphoma with implications for novel diagnostic or therapeutic strategies.
儿童型滤泡性淋巴瘤和儿童边缘区淋巴瘤是最罕见的两种B细胞淋巴瘤。这些淋巴瘤主要发生于儿童群体，具有与成人中更常见的对应类型（成人型滤泡性淋巴瘤和成人型结内边缘区淋巴瘤）不同的特征。在此，我们报告了一组儿童型滤泡性淋巴瘤和儿童边缘区淋巴瘤的详细全外显子深度测序分析。该分析揭示，在6例儿童型滤泡性淋巴瘤病例中有3例（50%）存在转录因子干扰素调节因子8（IRF8）中编码p.Lys66Arg的复发性体细胞变异。在儿童边缘区淋巴瘤或成人型滤泡性淋巴瘤中未检测到这种特定的点突变。在儿童型滤泡性淋巴瘤中，还观察到参与转录、细胞内信号传导和细胞增殖的基因存在其他体细胞点突变。在儿童边缘区淋巴瘤中，未发现复发性突变；然而，在参与细胞黏附、细胞因子调节元件和细胞增殖的基因中观察到体细胞点突变。在1例儿童边缘区淋巴瘤病例中还鉴定出脾边缘区淋巴瘤中反复突变的基因AMOTL1中的一个体细胞变异。儿童型滤泡性淋巴瘤和儿童边缘区淋巴瘤的总体非同义突变负担均较低（每个外显子4.6个突变）。总之，这些发现支持儿童型滤泡性淋巴瘤和儿童边缘区淋巴瘤与成人亚型相比以及它们彼此之间存在独特的遗传基础。此外，IRF8中复发性点突变的鉴定为儿童型滤泡性淋巴瘤发病机制中的潜在驱动突变提供了见解，对新的诊断或治疗策略具有启示意义。
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