GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation
GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation
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DOI：
10.1016/j.ajhg.2016.06.010
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发表时间：
2016-08-04
影响因子：
9.8
通讯作者：
Choate, Keith A.
中科院分区：
文献类型：
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作者：
Lim, Young H.;Bacchiocchi, Antonella;Choate, Keith A.
血管肿瘤是婴儿和儿童中最常见的肿瘤之一; 5%-10%的新生儿在出生后的前3个月内出现或发展病变。大多数是良性婴儿血管瘤，通常在5岁时消退;其他血管肿瘤包括先天性簇状血管瘤（TA）、卡波西样血管内皮瘤（KHE）和儿童小叶毛细血管瘤（LCH）。这些病变中的一些可以成为局部侵入性的，并且对药物干预无反应，导致严重的并发症。最近的研究表明，HRAS，KRAS，NRAS，GNAQ和GNA 11中的激活突变可导致某些类型的罕见儿童血管肿瘤，我们现在已经通过全外显子组和靶向测序确定了GNA 14中的因果复发性体细胞激活突变。我们在一个KHE、一个TA和一个LCH中发现了体细胞激活的GNA 14 c.614A>T（p.Gln205Leu）突变，在两个LCH病变中发现了GNA 11 c.547C>T（p.Arg183Cys）突变。我们通过在原代人内皮细胞和黑素细胞中表达突变型GNA 14或GNA 11来研究突变病理生物学。GNA 14和GNA 11突变诱导细胞形态的变化，并通过上调MAPK通路使细胞不依赖于生长因子。我们的研究结果确定了GNA 14突变是儿童血管肿瘤的原因，通过影响Gaq家族成员的突变提供了致癌转化机制的见解，并确定了治疗干预的潜在靶点。
Vascular tumors are among the most common neoplasms in infants and children; 5%-10% of newborns present with or develop lesions within the first 3 months of life. Most are benign infantile hemangiomas that typically regress by 5 years of age; other vascular tumors include congenital tufted angiomas (TAs), kaposiform hemangioendotheliomas (KHEs), and childhood lobular capillary hemangiomas (LCHs). Some of these lesions can become locally invasive and unresponsive to pharmacologic intervention, leading to significant complications. Recent investigation has revealed that activating mutations in HRAS, KRAS, NRAS, GNAQ, and GNA11 can cause certain types of rare childhood vascular tumors, and we have now identified causal recurrent somatic activating mutations in GNA14 by whole-exome and targeted sequencing. We found somatic activating GNA14 c.614A>T (p.Gln205Leu) mutations in one KHE, one TA, and one LCH and a GNA11 c.547C>T (p.Arg183Cys) mutation in two LCH lesions. We examined mutation pathobiology via expression of mutant GNA14 or GNA11 in primary human endothelial cells and melanocytes. GNA14 and GNA11 mutations induced changes in cellular morphology and rendered cells growth-factor independent by upregulating the MAPK pathway. Our findings identify GNA14 mutations as a cause of childhood vascular tumors, offer insight into mechanisms of oncogenic transformation by mutations affecting Gaq family members, and identify potential targets for therapeutic intervention.