@article{b5db77317d904b9c8dd1e7478f146c84,
title = "Clinical and mutational spectrum of highly differentiated, paired box 3:forkhead box protein o1 fusion–negative rhabdomyosarcoma: A report from the Children's Oncology Group",
abstract = "BACKGROUND: Pediatric paired box 3:forkhead box protein O1 fusion–negative (PF–) rhabdomyosarcoma (RMS) represents a diverse spectrum of tumors with marked differences in histology, myogenic differentiation, and clinical behavior. METHODS: This study sought to evaluate the clinical and mutational spectrum of 24 pediatric PF– human RMS tumors with high levels of myogenic differentiation. Tumors were sequenced with OncoPanel v.2, a panel consisting of the coding regions of 504 genes previously linked to human cancer. RESULTS: Most of the tumors (19 of 24) arose at head/neck or genitourinary sites, and the overall survival rate was 100% with a median follow-up time of 4.6 years (range, 1.4-8.6 years). RAS pathway gene mutations were the most common mutations in PF–, highly differentiated RMS tumors. In addition, Hedgehog (Hh) and mechanistic target of rapamycin (mTOR) gene mutations with evidence for functional relevance (high-impact) were identified in subsets of tumors. The presence of Hh and mTOR pathway gene mutations was mutually exclusive and was associated with high-impact RAS pathway gene mutations in 3 of 4 Hh-mutated tumors and in 1 of 6 mTOR-mutated tumors. CONCLUSIONS: Interestingly, Hh and mTOR gene mutations were previously associated with rhabdomyomas, which are also known to preferentially arise at head/neck and genitourinary sites. Findings from this study further support the idea that PF–, highly differentiated RMS tumors and rhabdomyomas may represent a continuous spectrum of tumors. Cancer 2018;124:1973-81.",
keywords = "Hedgehog signaling, RAS, mechanistic target of rapamycin (mTOR) signaling, rhabdomyoma, rhabdomyosarcoma, sequencing",
author = "Teot, {Lisa A.} and Michaela Schneider and Thorner, {Aaron R.} and Jing Tian and Chi, {Yueh Yun} and Matthew Ducar and Ling Lin and Marcin Wlodarski and Grier, {Holcombe E.} and Fletcher, {Christopher D.M.} and {van Hummelen}, Paul and Skapek, {Stephen X.} and Hawkins, {Douglas S.} and Wagers, {Amy J.} and Carlos Rodriguez-Galindo and Simone Hettmer",
note = "Funding Information: This work was funded in part by P.A.L.S. Bermuda/St. Baldrick's (to Simone Hettmer), by the Joslin Diabetes Center (to Amy J. Wagers), and by the National Cancer Institute (U10CA180886, U10CA180999, U10CA98543, and U10CA98413). Forty-one RMS cases labeled ?highly differentiated? or ?rhabdomyoma-like? were identified by L.A.T. during a central pathology review of tumors of children/adolescents enrolled in Children's Oncology Group (COG) RMS trials. Hematoxylin and eosin?stained sections were re-reviewed by L.A.T. to confirm the diagnosis of RMS as well as high levels of skeletal muscle differentiation (D3). In highly differentiated RMS tumors, myoblasts with ample eosinophilic, fibrillary cytoplasm were seen throughout tumor tissue, as previously described by Kodet et al. Two cases were PF+. Ultimately, D3 histology was confirmed in 24 PF? cases (Fig.). Corresponding normal tissue was not available. Data on the Intergroup Rhabdomyosarcoma Study stage and group, histology, primary tumor location, tumor size, age at diagnosis, sex, event-free survival (EFS), and overall survival (OS) were obtained from COG records (Table). Discarded normal human skeletal muscle, obtained from 7 donors without a tumor history, served as control samples. Two PF? RMS tumors, which exhibited only occasional, scattered myoblasts throughout the tumor tissue and did not meet the criteria for highly differentiated RMS, were obtained from the National Development and Research Institutes, Inc. All studies involving human tissue samples were approved by the relevant institutional review boards (protocol 12-496, Dana-Farber Cancer Institute; CHS#06-42 and CHS#08-21, Joslin Diabetes Center; and EA1/056/14, Charit?). Informed consent was obtained from each participant or each participant's guardian. Abbreviations: D3; advanced muscle differentiation features; IRS, Intergroup Rhabdomyosarcoma Study; NOS, not otherwise specified; RMS, rhabdomyosarcoma; PF-, paired box 3:forkhead box protein O1 fusion-negative. Forty-one RMS cases labeled ?highly differentiated? or ?rhabdomyoma-like? were identified by L.A.T. during a central pathology review of tumors of children/adolescents enrolled in Children's Oncology Group (COG) RMS trials. Hematoxylin and eosin?stained sections were re-reviewed by L.A.T. to confirm the diagnosis of RMS as well as high levels of skeletal muscle differentiation (D3). Publisher Copyright: {\textcopyright} 2018 American Cancer Society",
year = "2018",
month = may,
day = "1",
doi = "10.1002/cncr.31286",
language = "English (US)",
volume = "124",
pages = "1973--1981",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "9",
}