Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA.
Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA.
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DOI：
10.1016/j.jpeds.2014.12.069
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发表时间：
2015-04
影响因子：
5.1
通讯作者：
Murillo, Rudy
中科院分区：
文献类型：
--
作者：
Luks, Valerie L.;Kamitaki, Nolan;Vivero, Matthew P.;Uller, Wibke;Rab, Rashed;Bovee, Judith V. M. G.;Rialon, Kristy L.;Guevara, Carlos J.;Alomari, Ahmad I.;Greene, Arin K.;Fishman, Steven J.;Kozakewich, Harry P. W.;Maclellan, Reid A.;Mulliken, John B.;Rahbar, Reza;Spencer, Samantha A.;Trenor, Cameron C., III;Upton, Joseph;Zurakowski, David;Perkins, Jonathan A.;Kirsh, Andrew;Bennett, James T.;Dobyns, William B.;Kurek, Kyle C.;Warman, Matthew L.;McCarroll, Steven A.;Murillo, Rudy
为了验证体细胞PIK3CA突变会在包括孤立性淋巴畸形（LM）和Klippel-Trenaunay综合征（KTS）在内的更常见疾病患者中发现的假设。我们使用下一代测序、液滴数字PCR （ddPCR）和单分子分子转化探针（smMIPs）在波士顿儿童医院就诊的患者的受影响组织中寻找体细胞PIK3CA突变，这些患者患有分离的LM （n=17）、KTS （n=21）、纤维脂肪血管异常（FAVA, n=8）或先天性脂肪瘤过度生长并伴有血管、表皮和骨骼异常综合征（CLOVES, n= 33），我们首次发现了体细胞PIK3CA突变。我们还在西雅图儿童医院的第二组LM患者（n=31）中筛选了5个更常见的PIK3CA突变。波士顿儿童医院分离的LM（16/17）或LM作为综合征的一部分，如KTS (19/21)， FAVA（4/8）和CLOVES(30/32)，大多数个体为PIK3CA突变的体细胞嵌合，其中5种特异性PIK3CA突变占病例的80%。西雅图儿童医院74%的LM患者也存在5种特异性PIK3CA突变中的1种的体细胞嵌合。来自两个队列的许多受影响的组织标本含有少于10%的突变细胞。体细胞PIK3CA突变是孤立淋巴畸形和疾病的最常见原因，其中淋巴畸形是一个组成特征。五种PIK3CA突变占大多数病例。寻找因果突变需要对受影响的组织取样，以及能够检测低水平体细胞嵌合体的技术，因为畸形组织中突变细胞的丰度可能很低。
To test the hypothesis that somatic PIK3CA mutations would be found in patients with more common disorders including isolated lymphatic malformation (LM) and Klippel-Trenaunay syndrome (KTS). We used next generation sequencing, droplet digital PCR (ddPCR), and single molecule molecular inversion probes (smMIPs) to search for somatic PIK3CA mutations in affected tissue from patients seen at Boston Children’s Hospital who had an isolated LM (n=17), KTS (n=21), fibro-adipose vascular anomaly (FAVA; n=8), or congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (CLOVES; n = 33), the disorder for which we first identified somatic PIK3CA mutations. We also screened 5 of the more common PIK3CA mutations in a second cohort of patients with LM (n=31) from Seattle Children’s Hospital. Most individuals from Boston Children’s Hospital who had isolated LM (16/17) or LM as part of a syndrome, such as KTS (19/21), FAVA (4/8), and CLOVES (30/32) were somatic mosaic for PIK3CA mutations, with 5 specific PIK3CA mutations accounting for ~ 80% of cases. Seventy-four percent of patients with LM from Seattle Children’s Hospital also were somatic mosaic for 1 of 5 specific PIK3CA mutations. Many affected tissue specimens from both cohorts contained fewer than 10% mutant cells. Somatic PIK3CA mutations are the most common cause of isolated lymphatic malformations and disorders in which lymphatic malformation is a component feature. Five PIK3CA mutations account for most cases. The search for causal mutations requires sampling of affected tissues and techniques that are capable of detecting low-level somatic mosaicism, because the abundance of mutant cells in a malformed tissue can be low.
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通讯作者：
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Shendure J