Lisa A Teot1, Michaela Schneider2, Aaron R Thorner3, Jing Tian4, Yueh-Yun Chi4, Matthew Ducar3, Ling Lin3, Marcin Wlodarski2, Holcombe E Grier5, Christopher D M Fletcher6, Paul van Hummelen3, Stephen X Skapek7, Douglas S Hawkins8,9, Amy J Wagers10,11,12, Carlos Rodriguez-Galindo13, Simone Hettmer2. 1. Department of Pathology, Boston Children's Hospital, Boston, Massachusetts. 2. Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, Faculty of Medicine, University of Freiburg, Germany. 3. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts. 4. Department of Biostatistics, University of Florida, Gainesville, Florida. 5. Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts. 6. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. 7. Division of Hematology/Oncology, Children's Medical Center, University of Texas Southwestern Medical Center, Dallas, Texas. 8. Division of Hematology/Oncology, Seattle Children's Hospital, University of Washington, Seattle, Washington. 9. Fred Hutchinson Cancer Center, Seattle, Washington. 10. Harvard Stem Cell Institute, Cambridge, Massachusetts. 11. Department of Stem Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts. 12. Paul F. Glenn Center for the Biology of Aging at Harvard Medical School, Boston, Massachusetts. 13. Department of Global Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, Tennessee.
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.
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- humanRMS 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 humancancer. 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.
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