Molecular Heterogeneity in Pediatric Malignant Rhabdoid Tumors in Patients With Multi-Organ Involvement

Abstract

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 SMARCB1 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. SMARCB1 germline alterations were identified in all patients and in all tumors. We observed a second hit in SMARCB1 via 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 SMARCB1 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.

Recurrent spinal atypical teratoid/rhabdoid tumor with pulmonary metastasis

“…In addition, our patient developed extracranial metastases and treatment resistance, it may be better to consider rhabdoid predisposition syndrome, genetic and epigenetic profiling, and exploration of germline mutations in genes associated with rhabdoid predisposition syndrome (e.g., SMARCB1 or SMARCA4) could provide valuable insights. 20,28,29 Unfortunately, we could not perform such evaluations in the present case because the parents did not want them.…”

Rhabdoid tumor predisposition syndrome: A historical review of treatments and outcomes for associated pediatric malignancies

“…Gonadal mosaicism is thought to often account for inherited rhabdoid tumors, 8,10–12 but unusual reports of gain‐in‐function of SMARCB1 resulting in a similar phenotype have also been reported 13 . Case reports have found that not only do patients with synchronous rhabdoid tumors have varied methylation profiles, but also patients with metachronous rhabdoid tumors arising from RTPS, in which different DNA methylation patterns and copy number aberrations have been observed; these findings indicate that RTPS leads to non‐clonal formation of rhabdoid tumors 14,15 …”

“…13 Case reports have found that not only do patients with synchronous rhabdoid tumors have varied methylation profiles, but also patients with metachronous rhabdoid tumors arising from RTPS, in which different DNA methylation patterns and copy number aberrations have been observed; these findings indicate that RTPS leads to non-clonal formation of rhabdoid tumors. 14,15 Recent studies have characterized over 300 patients with ATRT and described prognostic molecular subdivisions (ATRT-SHH, ATRT-TYR, and ATRT-MYC) associated with the location of the tumor, average age of the patient, and specific genetic mutations. 16,17 More recently, ATRT samples were evaluated from a cohort of 325 patients from the Hospital for Sick Children in Toronto and 65 patients from the Children's Oncology Group (COG) study ACNS0333, and results validated the molecular subgroupings and revealed that the 16% of patients with germline mutations had a 4-year overall survival (OS) of only 20%.…”