INSERM U830, Laboratory of Translational Research in Pediatric Oncology, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center, Paris, France.
Somatic Genetic Unit, Department of Pathology and Diagnostic and Theranostic Medecine, PSL Research University, Institut Curie Hospital, Paris, France.
Neuro Oncol. 2024 Nov 4;26(11):2102-2112. doi: 10.1093/neuonc/noae122.
Rhabdoid tumors (RT) are aggressive, rare tumors predominantly affecting young children, characterized by biallelic SMARCB1 gene inactivation. While most SMARCB1 alterations are acquired de novo, a third of cases exhibit germline alterations, defining Rhabdoid Tumors Predisposition Syndrome. With the increased sensitivity of next-generation sequencing (NGS), mosaicisms in genes linked to genetic diseases are more detectable. This study focuses on exploring SMARCB1 germline alterations, notably mosaicism in blood samples of children with RT and in parents, using a custom NGS panel.
A cohort of 280 children and 140 parents with germline analysis was studied. Germline DNA from 111 children with RT and 32 parents were reanalyzed with a custom NGS panel with 1500X average depth targeting the SMARCB1 gene to identify intragenic variants not detected with conventional low-sensitivity methods. Follow-up data was obtained for 77 patients.
Nine previously undetected mosaicism cases were identified, totaling 17/280 patients with a mosaic variant (6.1%) in the cohort, with variant allele frequencies between 0.9% and 33%, thus highlighting the prior underestimation of its prevalence. Follow-up data showed that 4 out of 7 survivors with mosaic variants developed distinct novel tumors, 2 sharing SMARCB1 alterations with the initial tumor, emphasizing the potential clinical impact of SMARCB1 mosaicism.
The hitherto underestimated rate of SMARCB1 mosaicism in RT underscores the need for optimized genetic counseling and oncological monitoring. The findings have significant medical implications, considering the dire prognosis of RT.
横纹肌样瘤（RT）是一种侵袭性的、罕见的肿瘤，主要影响幼儿，其特征是双等位基因 SMARCB1 基因失活。虽然大多数 SMARCB1 改变是后天获得的，但三分之一的病例存在种系改变，定义了横纹肌样瘤易感性综合征。随着下一代测序（NGS）的敏感性增加，与遗传疾病相关的基因镶嵌现象更容易被检测到。本研究旨在使用定制的 NGS 面板探索 SMARCB1 种系改变，特别是儿童横纹肌样瘤和父母血液样本中的镶嵌现象。
研究了一组 280 名儿童和 140 名有胚系分析的父母。对 111 名 RT 儿童和 32 名父母的胚系 DNA 进行了重新分析，使用定制的 NGS 面板，平均深度为 1500X，靶向 SMARCB1 基因，以识别常规低灵敏度方法未检测到的基因内变异。对 77 例患者进行了随访数据。
共鉴定出 9 例先前未检测到的镶嵌现象，总计 280 例患者中有 17 例（6.1%）存在镶嵌变体，变异等位基因频率在 0.9%至 33%之间，因此突出了其发病率的先前低估。随访数据显示，4 例携带镶嵌变体的幸存者均出现了不同的新发肿瘤，其中 2 例与初始肿瘤共享 SMARCB1 改变，强调了 SMARCB1 镶嵌现象的潜在临床影响。
RT 中 SMARCB1 镶嵌现象的发病率被低估，这突显了需要优化遗传咨询和肿瘤监测。鉴于 RT 的预后较差，这些发现具有重要的医学意义。
