Abstract：
BACKGROUND: Rhabdoid tumors (RT) are aggressive, rare tumors predominantly affecting young children, characterized by bi-allelic SMARCB1 gene inactivation. While most SMARCB1 alterations are acquired de novo, a third of cases exhibit germline alterations, defining Rhabdoid Tumors Predisposition Syndrome (RTPS1). With 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.
METHODS: A cohort of 280 children and 140 parents with germline analysis was studied. Germline DNA from 111 children with RT and 32 parents were re-analyzed with a custom NGS panel with 1,500X 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.
RESULTS: 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, two sharing SMARCB1 alterations with the initial tumor, emphasizing the potential clinical impact of SMARCB1 mosaicism.
CONCLUSIONS: 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.
METHODS: A cohort of 280 children and 140 parents with germline analysis was studied. Germline DNA from 111 children with RT and 32 parents were re-analyzed with a custom NGS panel with 1,500X 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.
RESULTS: 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, two sharing SMARCB1 alterations with the initial tumor, emphasizing the potential clinical impact of SMARCB1 mosaicism.
CONCLUSIONS: 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.
摘要：
背景：横纹肌样肿瘤（RT）具有侵袭性，主要影响幼儿的罕见肿瘤，以双等位基因SMARCB1基因失活为特征。虽然大多数SMARCB1改变是从头获得的，三分之一的病例表现出种系改变，定义横纹肌样瘤易感综合征（RTPS1）。随着下一代测序（NGS）灵敏度的提高，与遗传疾病相关的基因中的镶嵌现象更容易被检测到。本研究的重点是探索SMARCB1种系改变，特别是患有RT的儿童和父母的血液样本中的镶嵌现象，使用自定义NGS面板。
方法：对280名儿童和140名父母进行种系分析。使用针对SMARCB1基因的平均深度为1,500X的定制NGS面板重新分析了来自111名RT儿童和32名父母的种系DNA，以鉴定常规低敏感性方法未检测到的基因内变异。获得了77例患者的随访数据。
结果：确定了9个以前未发现的镶嵌病病例，队列中共有17/280名患者出现马赛克变异（6.1%），变异等位基因频率在0.9%到33%之间，从而突出了对其流行率的事先低估。随访数据显示，7名具有马赛克变体的幸存者中有4人发展出不同的新型肿瘤，两个与初始肿瘤共享SMARCB1改变，强调SMARCB1镶嵌的潜在临床影响。
结论：迄今为止在RT中被低估的SMARCB1镶嵌率强调了优化遗传咨询和肿瘤监测的必要性。这些发现具有重大的医学意义，考虑到RT的可怕预后。
方法：对280名儿童和140名父母进行种系分析。使用针对SMARCB1基因的平均深度为1,500X的定制NGS面板重新分析了来自111名RT儿童和32名父母的种系DNA，以鉴定常规低敏感性方法未检测到的基因内变异。获得了77例患者的随访数据。
结果：确定了9个以前未发现的镶嵌病病例，队列中共有17/280名患者出现马赛克变异（6.1%），变异等位基因频率在0.9%到33%之间，从而突出了对其流行率的事先低估。随访数据显示，7名具有马赛克变体的幸存者中有4人发展出不同的新型肿瘤，两个与初始肿瘤共享SMARCB1改变，强调SMARCB1镶嵌的潜在临床影响。
结论：迄今为止在RT中被低估的SMARCB1镶嵌率强调了优化遗传咨询和肿瘤监测的必要性。这些发现具有重大的医学意义，考虑到RT的可怕预后。
