Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma
Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma
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DOI：
10.1016/j.ajhg.2016.03.009
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发表时间：
2016-04-07
影响因子：
9.8
通讯作者：
Warman, Matthew L.
中科院分区：
文献类型：
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作者：
Ayturk, Ugur M.;Couto, Javier A.;Warman, Matthew L.
先天性血管瘤是一种罕见的血管肿瘤，在子宫内形成。出生后，肿瘤要么迅速消退（即，快速消退的先天性血管瘤[RICH]）或部分消退和稳定（即，非退化性先天性血管瘤[NICH]）。我们假设先天性血管瘤是由于体细胞突变引起的，并对8名参与者的受影响组织进行了大规模平行mRNA测序。我们确定了互斥的，镶嵌错义突变，改变谷氨酰胺在氨基酸209（Glu 209）在GNAQ或GNA 11在所有测试的样品，在变异等位基因频率（VAF）范围从3%到33%。我们使用分子倒置探针测序（MIP-seq）和数字液滴PCR（ddPCR）的组合验证了基因组DNA中突变的存在。我们鉴定的Glu 209 GNAQ和GNA 11错义变体在葡萄膜黑色素瘤中是常见的，并且已经显示组成性激活MAPK和/或雅普信号传导。当我们筛选额外的档案福尔马林固定石蜡包埋（FFPE）先天性皮肤和肝脏血管瘤，4/8有GNAQ或GNA 11 Glu 209变异。在NICH和RICH中发现了相同的GNAQ或GNA 11突变，因此其他因素必须解释这些肿瘤不同的出生后行为。
Congenital hemangioma is a rare vascular tumor that forms in utero. Postnatally, the tumor either involutes quickly (i.e., rapidly involuting congenital hemangioma [RICH]) or partially regresses and stabilizes (i.e., non-involuting congenital hemangioma [NICH]). We hypothesized that congenital hemangiomas arise due to somatic mutation and performed massively parallel mRNA sequencing on affected tissue from eight participants. We identified mutually exclusive, mosaic missense mutations that alter glutamine at amino acid 209 (Glu209) in GNAQ or GNA11 in all tested samples, at variant allele frequencies (VAF) ranging from 3% to 33%. We verified the presence of the mutations in genomic DNA using a combination of molecular inversion probe sequencing (MIP-seq) and digital droplet PCR (ddPCR). The Glu209 GNAQ and GNA11 missense variants we identified are common in uveal melanoma and have been shown to constitutively activate MAPK and/or YAP signaling. When we screened additional archival formalin-fixed paraffin embedded (FFPE) congenital cutaneous and hepatic hemangiomas, 4/8 had GNAQ or GNA11 Glu209 variants. The same GNAQ or GNA11 mutation is found in both NICH and RICH, so other factors must account for these tumors' different postnatal behaviors.