TY - JOUR
T1 - Molecular Heterogeneity in Pediatric Malignant Rhabdoid Tumors in Patients With Multi-Organ Involvement
AU - Miller, Katherine E.
AU - Wheeler, Gregory
AU - LaHaye, Stephanie
AU - Schieffer, Kathleen M.
AU - Cearlock, Sydney
AU - Venkata, Lakshmi Prakruthi Rao
AU - Bravo, Alejandro Otero
AU - Grischow, Olivia E.
AU - Kelly, Benjamin J.
AU - White, Peter
AU - Pierson, Christopher R.
AU - Boué, Daniel R.
AU - Koo, Selene C.
AU - Klawinski, Darren
AU - Ranalli, Mark A.
AU - Shaikhouni, Ammar
AU - Salloum, Ralph
AU - Shatara, Margaret
AU - Leonard, Jeffrey R.
AU - Wilson, Richard K.
AU - Cottrell, Catherine E.
AU - Mardis, Elaine R.
AU - Koboldt, Daniel C.
N1 - Funding Information:
This work was supported by the Nationwide Foundation Pediatric Innovation Fund.
Publisher Copyright:
Copyright © 2022 Miller, Wheeler, LaHaye, Schieffer, Cearlock, Venkata, Bravo, Grischow, Kelly, White, Pierson, Boué, Koo, Klawinski, Ranalli, Shaikhouni, Salloum, Shatara, Leonard, Wilson, Cottrell, Mardis and Koboldt.
PY - 2022/7/13
Y1 - 2022/7/13
N2 - 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.
AB - 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.
KW - DNA methylation array
KW - SMARCB1
KW - atypical teratoid/rhabdoid tumor (AT/RT)
KW - malignant rhabdoid tumor (MRT)
KW - next-generation sequencing
UR - http://www.scopus.com/inward/record.url?scp=85135198255&partnerID=8YFLogxK
U2 - 10.3389/fonc.2022.932337
DO - 10.3389/fonc.2022.932337
M3 - Article
C2 - 35912263
AN - SCOPUS:85135198255
SN - 2234-943X
VL - 12
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 932337
ER -