Fleischmann Lara S, Nemes Karolina, Glaser Selina, Kouroukli Alexandra G, Boros Matej, Bens Susanne, Dahlum Sonja, Kretzmer Helene, Oyen Florian, Gerss Joachim, Hasselblatt Martin, Frühwald Michael C, Siebert Reiner
Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.
Bavarian Cancer Research Center (BZKF), Augsburg, Germany.
Neuro Oncol. 2025 Feb 10;27(2):533-544. doi: 10.1093/neuonc/noae188.
Malignant rhabdoid tumors (RT) are aggressive malignancies predominantly affecting very young children. The characteristic genetic alteration is the biallelic inactivation of SMARCB1. In approximately 30% of patients, one SMARCB1 allele is constitutionally altered conferring a particularly unfavorable prognosis. Constitutional mosaicism for pathogenic SMARCB1 mutations has recently been reported in distinct cases of allegedly sporadic RT. We aimed to systematically investigate the frequency and clinical impact of constitutional mosaicism in patients with sporadic RT included in the EU-RHAB registry.
We selected 29 patients with RT displaying at least one pathogenic small variant in SMARCB1 in the tumor DNA and the absence of a germline mutation. We re-screened blood-derived patients and controlled DNA for the respective small variant by polymerase chain reaction with unique molecular identifiers and ultra-deep next-generation sequencing. Clinical data in patients with and without mosaicism and 174 EU-RHAB controls were compared.
Employing an ultra-deep sequencing approach, we detected tumor-associated SMARCB1 variants in blood-derived DNA in 9/29 patients. In 6/29 patients (21%), whose variant allele frequency (VAF) exceeded 2%, constitutional mosaicism was assumed whereas tumor DNA contamination was documented in 1/3 of patients with VAF below 1%. No significant differences were observed between 6 mosaic-positive and 20 -negative patients regarding age at diagnosis, presence of metastases, event-free or overall survival.
Constitutional mosaicism for pathogenic small SMARCB1 variants is recurrent in patients with allegedly sporadic RT. The clinical implications of such variants need to be determined in larger, prospective cohorts also including detection of structural variants of SMARCB1.
恶性横纹肌样瘤（RT）是一种侵袭性恶性肿瘤，主要影响幼儿。其特征性基因改变是SMARCB1的双等位基因失活。在大约30%的患者中，一个SMARCB1等位基因发生先天性改变，预后特别差。最近在一些所谓散发型RT的不同病例中报道了致病性SMARCB1突变的先天性嵌合体。我们旨在系统研究纳入欧盟横纹肌样瘤（EU-RHAB）登记处的散发型RT患者中先天性嵌合体的频率及其临床影响。
我们选择了29例RT患者，这些患者的肿瘤DNA中SMARCB1至少有一个致病性小变异，且不存在种系突变。我们通过带有独特分子标识符的聚合酶链反应和超深度下一代测序，对血液来源患者的DNA重新筛查各自的小变异。比较了有和没有嵌合体的患者以及174名EU-RHAB对照的临床数据。
采用超深度测序方法，我们在29例患者中9例血液来源的DNA中检测到与肿瘤相关的SMARCB1变异。在6/29例患者（21%）中，其变异等位基因频率（VAF）超过2%，推测为先天性嵌合体，而在VAF低于1%的患者中有1/3记录到肿瘤DNA污染。在诊断年龄、转移情况、无事件生存或总生存方面，6例嵌合体阳性和20例阴性患者之间未观察到显著差异。
在所谓散发型RT患者中，致病性小SMARCB1变异的先天性嵌合体很常见。此类变异的临床意义需要在更大的前瞻性队列中确定，队列还应包括检测SMARCB1的结构变异。
