Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California.
Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Department of Pathology, Keck School of Medicine at the University of Southern California, Los Angeles, California.
Pediatr Neurol. 2021 Jan;114:55-59. doi: 10.1016/j.pediatrneurol.2020.09.015. Epub 2020 Oct 2.
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.
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.
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.
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.
由于体细胞镶嵌性引起的 PI3KCA 相关过度生长谱障碍与身体的节段性过度生长有关，伴有血管、骨骼和脑畸形，如巨脑回畸形。致病变异体可能仅在受影响的组织中检测到，而在外周血或唾液样本中检测不到；因此，存档组织可能是唯一可用于检测的相关样本。虽然这是癌症检测的常用方法，但通常不适用于遗传性遗传疾病。
使用专门为儿科肿瘤设计的下一代测序面板（OncoKids）评估 PI3KCA 镶嵌性，该面板旨在捕获儿科恶性肿瘤中的体细胞突变。该面板涵盖了广泛的目标，包括 PI3KCA 和 AKT1 热点。我们使用 OncoKids 对 7 名面部单侧肥大和脂肪瘤、巨脑回畸形或单侧肥大伴血管淋巴管畸形患者的存档福尔马林固定、石蜡包埋或冷冻样本进行检测。下一代测序检测的存档组织年龄从 2 岁到 13 岁不等（中位数 5 岁）。每个患者均表现出 PI3KCA 相关过度生长谱内的临床表现，并且在之前的手术干预中获得了受影响组织的样本进行检测。
在所有 7 名患者中均检测到 PI3KCA 镶嵌性，并且血管淋巴管畸形组织中的突变等位基因分数较低（8%至 11%），而脑（20%至 32%）和脂肪组织（16%至 23%）中的突变等位基因分数较高。
我们的研究强调了使用强大的肿瘤学重点下一代测序检测来识别非癌症病例中的 PI3KCA 镶嵌性的临床实用性。使用超过 10 年的存档样本获得分子诊断是可行的，这可以用于改善医疗保健管理。
