文章：

识别复发性儿童T淋巴母细胞白血病中一个遗传学定义的超高危群体

Identification of a genetically defined ultra-high-risk group in relapsed pediatric T-lymphoblastic leukemia

原文发布日期：2017-02-03

DOI: 10.1038/bcj.2017.3

类型: Original Article

开放获取: 是

英文摘要：

Recent genetic analysis has identified frequent mutations in ten-eleven translocation 2 (TET2), DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 2 (IDH2) and ras homolog family member A (RHOA) in nodal T-cell lymphomas, including angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified. We examined the distribution of mutations in these subtypes of mature T-/natural killer cell neoplasms to determine their clonal architecture. Targeted sequencing was performed for 71 genes in tumor-derived DNA of 87 cases. The mutations were then analyzed in a programmed death-1 (PD1)-positive population enriched with tumor cells and CD20-positive B cells purified by laser microdissection from 19 cases. TET2 and DNMT3A mutations were identified in both the PD1+ cells and the CD20+ cells in 15/16 and 4/7 cases, respectively. All the RHOA and IDH2 mutations were confined to the PD1+ cells, indicating that some, including RHOA and IDH2 mutations, being specific events in tumor cells. Notably, we found that all NOTCH1 mutations were detected only in the CD20+ cells. In conclusion, we identified both B- as well as T-cell-specific mutations, and mutations common to both T and B cells. These findings indicate the expansion of a clone after multistep and multilineal acquisition of gene mutations.

摘要翻译： 

为探寻儿童T细胞急性淋巴细胞白血病（T-ALL）复发的关键环节基因及其预后标志物，我们对214例患者进行了313个白血病相关基因的靶向测序：其中67份样本采集于复发期，147份采集于初诊时。作为复发特异性遗传事件，我们在32/67的T-ALL复发样本中鉴定出NT5C2激活突变（P=0.0001，Fisher精确检验）、TP53失活突变（P=0.0007，Fisher精确检验）及chr17:q11.2-24.3区段扩增（P=0.0068，Fisher精确检验）。TP53变异多为纯合事件，与野生型TP53相比，该类变异显著关联其他基因更高的拷贝数变异率（P=0.0004，Mann-Whitney检验）。我们进一步聚焦具有预后影响的突变，发现调控DNA完整性的基因（TP53，n=8；USP7，n=4；MSH6，n=4）、RAS信号通路关键基因（KRAS、NRAS，n=8）以及IL7R（n=4）和CNOT3（n=4）仅在致死性复发病例中出现突变。这些标志物可识别24/49的二次事件患者。其中17例患者主要表现为难治性复发，亟需有效治疗方案，我们为其鉴定出个性化治疗的候选靶点：p53再激活化合物、MEK抑制剂或JAK/STAT抑制剂，这些靶点可能纳入未来治疗策略。

原文链接：

Identification of a genetically defined ultra-high-risk group in relapsed pediatric T-lymphoblastic leukemia