Rhabdomyosarcoma study with WXS data on dbGaP (621 participants)

phs002304 — Germline and Somatic Genetic Landscape of Pediatric Rhabdomyosarcoma

Dynamic approaches that integrate population-based research and molecular biology are needed to explain the mechanisms underlying pediatric rhabdomyosarcoma (RMS) and to determine novel prevention strategies. RMS, the most common soft-tissue sarcoma in children and adolescents, has one of the poorest 5-year survival rates among all pediatric cancers (less than 65%). One of the strongest risk factors for RMS is having a cancer predisposition syndrome. The syndromes that are most commonly seen among those with RMS are Li-Fraumeni, neurofibromatosis type 1, Costello, Noonan, and DICER1. Based on smaller clinic-based studies, only about 7% of RMS cases are thought to be associated with the genes responsible for these syndromes. However, there have been no population-based assessments to support this estimate. Even in the most recent large-scale evaluations of germline mutations in predisposition genes among children with cancer, very few RMS cases were included (43 cases). Furthermore, no distinctions were made between the major histologic subtypes of RMS: embryonal (eRMS) and alveolar (aRMS), which display differences in terms of age distribution, incidence, and cytogenetics. For instance, nearly 80% of alveolar cases are driven by a chromosomal translocation between either PAX3 or PAX7 and FOXO1, whereas these fusions are not seen in embryonal cases. In fact, RMS research is shifting from categorization based on histology to fusion status (eRMS is overwhelmingly fusion-negative). Another limitation in previous studies has been the inability to evaluate the frequency of de novo germline mutations (DNMs) in cancer predisposition genes due to the absence of any well-characterized cohorts of RMS case-parent trios. Therefore, a major gap in our understanding of the role of cancer predisposition in pediatric RMS that limit translational impact is there have been no population-based assessments to determine the true impact of these mutations on pediatric RMS, which limits clinical sequencing guidelines and surveillance protocols in these children. Overall Project Strategy: The objective of this project is to advance our understanding of the relationship between cancer predisposition genes and pediatric RMS. Our central hypotheses are: 1) mutations in cancer predisposition genes are more common than expected in children with RMS; and 2) children with fusion-negative tumors have a higher burden of germline mutations than those with fusion-positive tumors. The framework for this study relies on >600 well annotated samples collected from newly diagnosed RMS patients and stored in the Children’s Oncology Group (COG) Biopathology Center.