Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene
Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene
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DOI：
10.3324/haematol.2015.135475
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发表时间：
2016-07-01
期刊：
影响因子：
10.1
通讯作者：
Goldin, Lynn R.
中科院分区：
文献类型：
--
作者：
Rotunno, Melissa;McMaster, Mary L.;Goldin, Lynn R.
霍奇金淋巴瘤具有很强的家族聚集性，但迄今为止尚未发现主要的易感基因。本研究的目的是使用全外显子组测序在 17 个有 3 个或更多受影响病例或必然携带者（69 个人）的霍奇金淋巴瘤易发家庭中识别高外显率变异，然后对另外 48 个较小的 HL 家庭（80 个人）进行靶向测序。使用标准方法进行比对和变体调用。根据预测的有害性、保守性和淋巴恶性肿瘤途径中的潜在重要性，进一步对显性分离、罕见、编码或潜在功能性变异进行优先排序。我们选择了23个基因进行靶向测序。只有 KDR（激酶插入结构域受体）也称为 VEGFR2（血管内皮生长因子受体 2）中的 p.A1065T 变体在两个独立的霍奇金淋巴瘤家族中被复制。 KDR 是一种 III 型受体酪氨酸激酶，是血管内皮生长因子诱导增殖、存活和迁移的主要介质。它的活性与包括淋巴瘤在内的多种疾病有关。功能实验表明，位于激活环中的 p.A1065T 在没有血管内皮生长因子的情况下可以促进酪氨酸的组成型自磷酸化，并且在暴露于激酶抑制剂后激酶活性被消除。还发现了其他一些有希望的突变，但似乎是“私人的”。总之，在迄今为止最大的霍奇金淋巴瘤家族测序队列中，我们发现了 KDR 基因的因果突变。虽然需要独立验证，但这种突变可能会增加下游肿瘤细胞增殖活性，并可能成为靶向治疗的候选者。
Hodgkin lymphoma shows strong familial aggregation but no major susceptibility genes have been identified to date. The goal of this study was to identify high-penetrance variants using whole exome sequencing in 17 Hodgkin lymphoma prone families with three or more affected cases or obligate carriers (69 individuals), followed by targeted sequencing in an additional 48 smaller HL families (80 individuals). Alignment and variant calling were performed using standard methods. Dominantly segregating, rare, coding or potentially functional variants were further prioritized based on predicted deleteriousness, conservation, and potential importance in lymphoid malignancy pathways. We selected 23 genes for targeted sequencing. Only the p.A1065T variant in KDR (kinase insert domain receptor) also known as VEGFR2 (vascular endothelial growth factor receptor 2) was replicated in two independent Hodgkin lymphoma families. KDR is a type III receptor tyrosine kinase, the main mediator of vascular endothelial growth factor induced proliferation, survival, and migration. Its activity is associated with several diseases including lymphoma. Functional experiments have shown that p.A1065T, located in the activation loop, can promote constitutive autophosphorylation on tyrosine in the absence of vascular endothelial growth factor and that the kinase activity was abrogated after exposure to kinase inhibitors. A few other promising mutations were identified but appear to be "private". In conclusion, in the largest sequenced cohort of Hodgkin lymphoma families to date, we identified a causal mutation in the KDR gene. While independent validation is needed, this mutation may increase downstream tumor cell proliferation activity and might be a candidate for targeted therapy.