Miller Katherine E, Wheeler Gregory, LaHaye Stephanie, Schieffer Kathleen M, Cearlock Sydney, Venkata Lakshmi Prakruthi Rao, Bravo Alejandro Otero, Grischow Olivia E, Kelly Benjamin J, White Peter, Pierson Christopher R, Boué Daniel R, Koo Selene C, Klawinski Darren, Ranalli Mark A, Shaikhouni Ammar, Salloum Ralph, Shatara Margaret, Leonard Jeffrey R, Wilson Richard K, Cottrell Catherine E, Mardis Elaine R, Koboldt Daniel C
The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, United States.
Front Oncol. 2022 Jul 13;12:932337. doi: 10.3389/fonc.2022.932337. eCollection 2022.
Rhabdoid tumors (RTs) of the brain (atypical teratoid/rhabdoid tumor; AT/RT) and extracranial sites (most often the kidney; RTK) are malignant tumors predominantly occurring in children, frequently those with germline alterations. Here we present data from seven RTs from three pediatric patients who all had multi-organ involvement. The tumors were analyzed using a multimodal molecular approach, which included exome sequencing of tumor and germline comparator and RNA sequencing and DNA array-based methylation profiling of tumors. germline alterations were identified in all patients and in all tumors. We observed a second hit in chr22 loss of heterozygosity. By methylation profiling, all tumors were classified as rhabdoid tumors with a corresponding subclassification within the MYC, TYR, or SHH AT/RT subgroups. Using RNA-seq gene expression clustering, we recapitulated the classification of known AT/RT subgroups. Synchronous brain and kidney tumors from the same patient showed different patterns of either copy number variants, single-nucleotide variants, and/or genome-wide DNA methylation, suggestive of non-clonal origin. Furthermore, we demonstrated that a lung and abdominal metastasis from two patients shared overlapping molecular features with the patient's primary kidney tumor, indicating the likely origin of the metastasis. In addition to the events, we identified other whole-chromosome events and single-nucleotide variants in tumors, but none were found to be prognostic, diagnostic, or offer therapeutic potential for rhabdoid tumors. While our findings are of biological interest, there may also be clinical value in comprehensive molecular profiling in patients with multiple rhabdoid tumors, particularly given the potential prognostic and therapeutic implications for different rhabdoid tumor subgroups demonstrated in recent clinical trials and other large cohort studies.
脑横纹肌样瘤（RTs，非典型畸胎样/横纹肌样瘤；AT/RT）和颅外部位的横纹肌样瘤（最常见于肾脏；RTK）是主要发生在儿童中的恶性肿瘤，尤其是那些具有种系改变的儿童。本文展示了来自三名儿科患者的七个RTs的数据，这些患者均有多器官受累。使用多模态分子方法对肿瘤进行分析，该方法包括肿瘤和种系对照的外显子组测序以及肿瘤的RNA测序和基于DNA阵列的甲基化分析。在所有患者和所有肿瘤中均鉴定出种系改变。我们观察到22号染色体杂合性缺失的第二次打击。通过甲基化分析，所有肿瘤均被分类为横纹肌样瘤，并在MYC、TYR或SHH AT/RT亚组中有相应的亚分类。使用RNA-seq基因表达聚类，我们重现了已知AT/RT亚组的分类。同一患者的同步脑和肾肿瘤显示出不同的拷贝数变异、单核苷酸变异和/或全基因组DNA甲基化模式，提示其非克隆起源。此外，我们证明两名患者的肺和腹部转移灶与患者的原发性肾肿瘤具有重叠的分子特征，表明转移灶可能的起源。除了这些事件外，我们在肿瘤中鉴定出其他全染色体事件和单核苷酸变异，但未发现它们对横纹肌样瘤具有预后、诊断或治疗潜力。虽然我们的发现具有生物学意义，但对于患有多个横纹肌样瘤的患者进行全面分子分析可能也具有临床价值，特别是考虑到最近的临床试验和其他大型队列研究中不同横纹肌样瘤亚组的潜在预后和治疗意义。
