Background

Disorders in the PIK3CA-related overgrowth spectrum because of somatic mosaicism are associated with segmental overgrowth of the body in conjunction with vascular, skeletal, and brain malformations such as hemimegalencephaly. A pathogenic variant may only be detectable in affected tissue and not in peripheral blood or saliva samples; therefore archival tissue may be the only relevant available specimen for testing. Although this is a common approach for cancer testing, it is not typically used for constitutional genetic disorders.

Methods

PIK3CA mosaicism was assessed with a custom pediatric oncology next-generation sequencing panel (OncoKids) designed to capture somatic mutations in pediatric malignancies. The panel covers a wide range of targets including PIK3CA and AKT1 hotspots. We used OncoKids on archival formalin-fixed, paraffin-embedded or frozen samples from seven patients with facial hemihypertrophy and lipomas, hemimegalencephaly, or hemihypertrophy with a lymphovascular malformation. The age of the archival tissue examined by next-generation sequencing ranged from two to 13 years (median 5 years). Every patient had clinical manifestations within the PIK3CA-related overgrowth spectrum and had a sample of an affected tissue available for testing from a prior surgical intervention.

Results

PIK3CA mosaicism was detected in all seven patients and the mutant allele fraction was lower in the lymphovascular malformation tissues (8% to 11%) than in brain (20% to 32%) and lipomatous (16% to 23%) tissues.

Conclusions

Our study highlights the clinical utility of using a robust, oncology-focused next-generation sequencing assay to identify PIK3CA mosaicism in noncancer cases. It is feasible to use archival samples that are more than a decade old to obtain a molecular diagnosis, which can then be used to improve health care management.

中文翻译：

---

定制小儿肿瘤学下一代测序面板可识别档案组织中的体细胞镶嵌现象并增强靶向临床护理

背景

由于体细胞嵌合现象导致的PIK3CA相关过度生长谱中的疾病与身体的节段性过度生长以及血管、骨骼和脑畸形（如半巨脑畸形）有关。致病性变异可能只能在受影响的组织中检测到，而不能在外周血或唾液样本中检测到；因此，档案组织可能是唯一可用于测试的相关样本。虽然这是癌症检测的常用方法，但它通常不用于体质性遗传疾病。

方法

PIK3CA嵌合体使用定制的儿科肿瘤学下一代测序面板 (OncoKids) 进行评估，该面板旨在捕获儿科恶性肿瘤的体细胞突变。该面板涵盖了广泛的目标，包括PIK3CA和AKT1热点。我们将 OncoKids 用于 7 名患有面部偏侧肥大和脂肪瘤、偏侧巨脑畸形或伴有淋巴管畸形的偏侧肥大患者的存档福尔马林固定、石蜡包埋或冷冻样本。通过下一代测序检查的档案组织的年龄范围为 2 至 13 年（中位数为 5 年）。每名患者都有PIK3CA内的临床表现-相关的过度生长谱，并有一个受影响的组织样本，可用于从先前的手术干预中进行测试。

结果

在所有 7 名患者中都检测到PIK3CA嵌合体，并且在淋巴血管畸形组织（8% 至 11%）中的突变等位基因分数低于脑（20% 至 32%）和脂肪瘤（16% 至 23%）组织中的突变等位基因分数。

结论

我们的研究强调了使用强大的、以肿瘤学为重点的下一代测序分析来识别非癌症病例中的PIK3CA嵌合体的临床效用。使用十年以上的档案样本进行分子诊断是可行的，然后可以用于改善医疗保健管理。