TY - JOUR
T1 - Genomic Classification and Clinical Outcome in Rhabdomyosarcoma
T2 - A Report From an International Consortium
AU - Shern, Jack F.
AU - Selfe, Joanna
AU - Izquierdo, Elisa
AU - Patidar, Rajesh
AU - Chou, Hsien Chao
AU - Song, Young K.
AU - Yohe, Marielle E.
AU - Sindiri, Sivasish
AU - Wei, Jun
AU - Wen, Xinyu
AU - Rudzinski, Erin R.
AU - Barkauskas, Donald A.
AU - Lo, Tammy
AU - Hall, David
AU - Linardic, Corinne M.
AU - Hughes, Debbie
AU - Jamal, Sabri
AU - Jenney, Meriel
AU - Chisholm, Julia
AU - Brown, Rebecca
AU - Jones, Kristine
AU - Hicks, Belynda
AU - Angelini, Paola
AU - George, Sally
AU - Chesler, Louis
AU - Hubank, Michael
AU - Kelsey, Anna
AU - Gatz, Susanne A.
AU - Skapek, Stephen X.
AU - Hawkins, Douglas S.
AU - Shipley, Janet M.
AU - Khan, Javed
N1 - Publisher Copyright:
Copyright © 2022 American Society of Clinical Oncology. All rights reserved.
PY - 2021/9/10
Y1 - 2021/9/10
N2 - PURPOSE Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent disease remains poor, and beyond PAXFOXO1 fusion status, no genomic markers are available for risk stratification. We present an international consortium study designed to determine the incidence of driver mutations and their association with clinical outcome. PATIENTS AND METHODS Tumor samples collected from patients enrolled on Children’s Oncology Group trials (1998-2017) and UK patients enrolled on malignant mesenchymal tumor and RMS2005 (1995-2016) trials were subjected to custom-capture sequencing. Mutations, indels, gene deletions, and amplifications were identified, and survival analysis was performed. RESULTS DNA from 641 patients was suitable for analyses. A median of one mutation was found per tumor. In FOXO1 fusion-negative cases, mutation of any RAS pathway member was found in . 50% of cases, and 21% had no putative driver mutation identified. BCOR (15%), NF1 (15%), and TP53 (13%) mutations were found at a higher incidence than previously reported and TP53 mutations were associated with worse outcomes in both fusion-negative and FOXO1 fusion-positive cases. Interestingly, mutations in RAS isoforms predominated in infants, 1 year (64% of cases). Mutation of MYOD1 was associated with histologic patterns beyond those previously described, older age, head and neck primary site, and a dismal survival. Finally, we provide a searchable companion database (ClinOmics), containing all genomic variants, and clinical annotation including survival data. CONCLUSION This is the largest genomic characterization of clinically annotated rhabdomyosarcoma tumors to date and provides prognostic genetic features that refine risk stratification and will be incorporated into prospective trials.
AB - PURPOSE Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent disease remains poor, and beyond PAXFOXO1 fusion status, no genomic markers are available for risk stratification. We present an international consortium study designed to determine the incidence of driver mutations and their association with clinical outcome. PATIENTS AND METHODS Tumor samples collected from patients enrolled on Children’s Oncology Group trials (1998-2017) and UK patients enrolled on malignant mesenchymal tumor and RMS2005 (1995-2016) trials were subjected to custom-capture sequencing. Mutations, indels, gene deletions, and amplifications were identified, and survival analysis was performed. RESULTS DNA from 641 patients was suitable for analyses. A median of one mutation was found per tumor. In FOXO1 fusion-negative cases, mutation of any RAS pathway member was found in . 50% of cases, and 21% had no putative driver mutation identified. BCOR (15%), NF1 (15%), and TP53 (13%) mutations were found at a higher incidence than previously reported and TP53 mutations were associated with worse outcomes in both fusion-negative and FOXO1 fusion-positive cases. Interestingly, mutations in RAS isoforms predominated in infants, 1 year (64% of cases). Mutation of MYOD1 was associated with histologic patterns beyond those previously described, older age, head and neck primary site, and a dismal survival. Finally, we provide a searchable companion database (ClinOmics), containing all genomic variants, and clinical annotation including survival data. CONCLUSION This is the largest genomic characterization of clinically annotated rhabdomyosarcoma tumors to date and provides prognostic genetic features that refine risk stratification and will be incorporated into prospective trials.
UR - http://www.scopus.com/inward/record.url?scp=85115381141&partnerID=8YFLogxK
U2 - 10.1200/JCO.20.03060
DO - 10.1200/JCO.20.03060
M3 - Article
C2 - 34166060
AN - SCOPUS:85115381141
SN - 0732-183X
VL - 39
SP - 2859
EP - 2871
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 26
ER -