He Li1, Saumya D Sisoudiya2,3,4, Bailey A Martin-Giacalone2, Michael M Khayat1,3, Shannon Dugan-Perez1, Deborah A Marquez-Do2, Michael E Scheurer2,4, Donna Muzny1, Eric Boerwinkle1,5, Richard A Gibbs1,3, Yueh-Yun Chi6, Donald A Barkauskas7,8, Tammy Lo7, David Hall7, Douglas R Stewart9, Joshua D Schiffman10, Stephen X Skapek11, Douglas S Hawkins12, Sharon E Plon1,2,3, Aniko Sabo1, Philip J Lupo2,4. 1. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. 2. Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, USA. 3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. 4. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. 5. School of Public Health, the University of Texas Health Science Center, Houston, TX, USA. 6. Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA. 7. QuadW Childhood Sarcoma Biostatistics and Annotation Office at the Children's Oncology Group, Monrovia, CA, USA. 8. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 9. Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. 10. Departments of Pediatrics and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. 11. Department of Pediatrics, the University of Texas Southwestern Medical Center, Dallas, TX, USA. 12. Division of Hematology-Oncology, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
Abstract
BACKGROUND: Several cancer-susceptibility syndromes are reported to underlie pediatric rhabdomyosarcoma (RMS); however, to our knowledge there have been no systematic efforts to characterize the heterogeneous genetic etiologies of this often-fatal malignancy. METHODS: We performed exome-sequencing on germline DNA from 615 patients with newly diagnosed RMS consented through the Children's Oncology Group. We compared the prevalence of cancer predisposition variants in 63 autosomal-dominant cancer predisposition genes in these patients with population controls (n = 9963). All statistical tests were 2-sided. RESULTS: We identified germline cancer predisposition variants in 45 RMS patients (7.3%; all FOXO1 fusion negative) across 15 autosomal dominant genes, which was statistically significantly enriched compared with controls (1.4%, P = 1.3 × 10-22). Specifically, 73.3% of the predisposition variants were found in predisposition syndrome genes previously associated with pediatric RMS risk, such as Li-Fraumeni syndrome (TP53) and neurofibromatosis type I (NF1). Notably, 5 patients had well-described oncogenic missense variants in HRAS (p.G12V and p.G12S) associated with Costello syndrome. Also, genetic etiology differed with histology, as germline variants were more frequent in embryonal vs alveolar RMS patients (10.0% vs 3.0%, P = .02). Although patients with a cancer predisposition variant tended to be younger at diagnosis (P = 9.9 × 10-4), 40.0% of germline variants were identified in those older than 3 years of age, which is in contrast to current genetic testing recommendations based on early age at diagnosis. CONCLUSIONS: These findings demonstrate that genetic risk of RMS results from germline predisposition variants associated with a wide spectrum of cancer susceptibility syndromes. Germline genetic testing for children with RMS should be informed by RMS subtypes and not be limited to only young patients.
BACKGROUND: Several cancer-susceptibility syndromes are reported to underlie pediatric rhabdomyosarcoma (RMS); however, to our knowledge there have been no systematic efforts to characterize the heterogeneous genetic etiologies of this often-fatal malignancy. METHODS: We performed exome-sequencing on germline DNA from 615 patients with newly diagnosed RMS consented through the Children's Oncology Group. We compared the prevalence of cancer predisposition variants in 63 autosomal-dominant cancer predisposition genes in these patients with population controls (n = 9963). All statistical tests were 2-sided. RESULTS: We identified germline cancer predisposition variants in 45 RMS patients (7.3%; all FOXO1 fusion negative) across 15 autosomal dominant genes, which was statistically significantly enriched compared with controls (1.4%, P = 1.3 × 10-22). Specifically, 73.3% of the predisposition variants were found in predisposition syndrome genes previously associated with pediatric RMS risk, such as Li-Fraumeni syndrome (TP53) and neurofibromatosis type I (NF1). Notably, 5 patients had well-described oncogenic missense variants in HRAS (p.G12V and p.G12S) associated with Costello syndrome. Also, genetic etiology differed with histology, as germline variants were more frequent in embryonal vs alveolar RMS patients (10.0% vs 3.0%, P = .02). Although patients with a cancer predisposition variant tended to be younger at diagnosis (P = 9.9 × 10-4), 40.0% of germline variants were identified in those older than 3 years of age, which is in contrast to current genetic testing recommendations based on early age at diagnosis. CONCLUSIONS: These findings demonstrate that genetic risk of RMS results from germline predisposition variants associated with a wide spectrum of cancer susceptibility syndromes. Germline genetic testing for children with RMS should be informed by RMS subtypes and not be limited to only young patients.
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