Boston, Mass. From the Departments of Plastic and Oral Surgery, Orthopaedic Surgery, and Pathology and Howard Hughes Medical Institute, Boston Children's Hospital; and the Department of Genetics, Harvard Medical School.
Plast Reconstr Surg. 2014 Jan;133(1):12e-19e. doi: 10.1097/01.prs.0000436822.26709.7c.
Facial infiltrating lipomatosis is a nonheritable disorder characterized by hemifacial soft-tissue and skeletal overgrowth, precocious dental development, macrodontia, hemimacroglossia, and mucosal neuromas. The authors tested the hypothesis that this condition is caused by a somatic mutation in the phosphatidylinositide-3 kinase (PI3K) signaling pathway, which has been indicted in other anomalies with overgrowth.
The authors extracted DNA from abnormal tissue in six individuals, generated sequencing libraries, enriched the libraries for 26 genes involved in the PI3K pathway, and designed and applied a sequential filtering strategy to analyze the sequence data for mosaic mutations.
Unfiltered sequence data contained variant reads affecting ~12 percent of basepairs in the targeted genes. Filtering reduced the fraction of targeted basepairs containing variant reads to ~0.008 percent, allowing the authors to identify causal missense mutations in PIK3CA (p.E453K, p.E542K, p.H1047R, or p.H1047L) in each affected tissue sample.
Affected tissue from individuals with facial infiltrating lipomatosis contains PIK3CA mutations that have previously been reported in cancers and in affected tissue from other nonheritable, overgrowth disorders, including congenital lipomatous overgrowth, vascular, epidermal, and skeletal anomalies syndrome, Klippel-Trenaunay syndrome, hemimegalencephaly, fibroadipose overgrowth, and macrodactyly. Because PIK3CA encodes a catalytic subunit of PI3K, and in vitro studies have shown that the overgrowth-associated mutations increase this enzyme's activity, PI3K inhibitors currently in clinical trials for patients with cancer may have a therapeutic role in patients with facial infiltrating lipomatosis. The strategy used to identify somatic mutations in patients with facial infiltrating lipomatosis is applicable to other somatic mosaic disorders that have allelic heterogeneity.
面部浸润性脂肪瘤病是一种非遗传性疾病，其特征为单侧面部软组织和骨骼过度生长、牙齿发育过早、巨牙症、巨舌症和黏膜神经瘤。作者检验了这样一个假设，即这种疾病是由磷脂酰肌醇 3-激酶（PI3K）信号通路中的体细胞突变引起的，该突变已在其他过度生长相关的异常中被证实。
作者从 6 名个体的异常组织中提取 DNA，生成测序文库，对涉及 PI3K 通路的 26 个基因进行文库富集，并设计和应用了一种连续过滤策略来分析镶嵌突变的序列数据。
未过滤的序列数据包含影响靶向基因约 12%碱基的变异读段。过滤后，靶向基因中含变异读段的比例降低至约 0.008%，使作者能够在每个受影响的组织样本中鉴定出 PIK3CA 的致病错义突变（p.E453K、p.E542K、p.H1047R 或 p.H1047L）。
面部浸润性脂肪瘤病患者的受影响组织中含有 PIK3CA 突变，这些突变先前已在癌症以及其他非遗传性、过度生长性疾病的受影响组织中被报道，包括先天性脂肪过多性过度生长、血管、表皮和骨骼异常综合征、Klippel-Trenaunay 综合征、偏侧巨脑症、纤维脂肪过度生长和巨指（趾）症。由于 PIK3CA 编码 PI3K 的催化亚基，并且体外研究表明，与过度生长相关的突变增加了该酶的活性，因此目前正在癌症患者中进行临床试验的 PI3K 抑制剂可能在面部浸润性脂肪瘤病患者中具有治疗作用。用于鉴定面部浸润性脂肪瘤病患者体细胞突变的策略适用于具有等位基因异质性的其他体细胞镶嵌性疾病。
