Frontiers in Oncology (Sep 2024)
Molecular characterization of gliomas and glioneuronal tumors amid Noonan syndrome: cancer predisposition examined
- Margaret Shatara,
- Kathleen M. Schieffer,
- Kathleen M. Schieffer,
- Kathleen M. Schieffer,
- Marilena Melas,
- Elizabeth A. Varga,
- Diana Thomas,
- Diana Thomas,
- Brianna A. Bucknor,
- Heather M. Costello,
- Gregory Wheeler,
- Benjamin J. Kelly,
- Katherine E. Miller,
- Katherine E. Miller,
- Diana P. Rodriguez,
- Mariam T. Mathew,
- Mariam T. Mathew,
- Mariam T. Mathew,
- Kristy Lee,
- Kristy Lee,
- Kristy Lee,
- Erin Crotty,
- Sarah Leary,
- Vera A. Paulson,
- Bonnie Cole,
- Mohamed S. Abdelbaki,
- Jonathan L. Finlay,
- Margot A. Lazow,
- Margot A. Lazow,
- Ralph Salloum,
- Ralph Salloum,
- Maryam Fouladi,
- Maryam Fouladi,
- Daniel R. Boué,
- Daniel R. Boué,
- Elaine R. Mardis,
- Elaine R. Mardis,
- Catherine E. Cottrell,
- Catherine E. Cottrell,
- Catherine E. Cottrell
Affiliations
- Margaret Shatara
- The Division of Hematology and Oncology, St. Louis Children’s Hospital, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
- Kathleen M. Schieffer
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
- Kathleen M. Schieffer
- Department of Pathology, The Ohio State University, Columbus, OH, United States
- Kathleen M. Schieffer
- Department of Pediatrics, The Ohio State University, Columbus, OH, United States
- Marilena Melas
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
- Elizabeth A. Varga
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
- Diana Thomas
- Department of Pathology, The Ohio State University, Columbus, OH, United States
- Diana Thomas
- Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
- Brianna A. Bucknor
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
- Heather M. Costello
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
- Gregory Wheeler
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
- Benjamin J. Kelly
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
- Katherine E. Miller
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
- Katherine E. Miller
- Department of Pediatrics, The Ohio State University, Columbus, OH, United States
- Diana P. Rodriguez
- The Department of Radiology, Nationwide Children’s Hospital, Columbus, OH, United States
- Mariam T. Mathew
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
- Mariam T. Mathew
- Department of Pathology, The Ohio State University, Columbus, OH, United States
- Mariam T. Mathew
- Department of Pediatrics, The Ohio State University, Columbus, OH, United States
- Kristy Lee
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
- Kristy Lee
- Department of Pathology, The Ohio State University, Columbus, OH, United States
- Kristy Lee
- Department of Pediatrics, The Ohio State University, Columbus, OH, United States
- Erin Crotty
- Division of Pediatric Hematology, Oncology, Bone Marrow Transplant and Cellular Therapy, Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, WA, United States
- Sarah Leary
- Division of Pediatric Hematology, Oncology, Bone Marrow Transplant and Cellular Therapy, Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, WA, United States
- Vera A. Paulson
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, United States
- Bonnie Cole
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, United States
- Mohamed S. Abdelbaki
- The Division of Hematology and Oncology, St. Louis Children’s Hospital, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
- Jonathan L. Finlay
- The Division of Hematology/Oncology, and Bone Marrow Transplantation, Nationwide Children’s Hospital and The Ohio State University, Columbus, OH, United States
- Margot A. Lazow
- Department of Pediatrics, The Ohio State University, Columbus, OH, United States
- Margot A. Lazow
- The Division of Hematology/Oncology, and Bone Marrow Transplantation, Nationwide Children’s Hospital and The Ohio State University, Columbus, OH, United States
- Ralph Salloum
- Department of Pediatrics, The Ohio State University, Columbus, OH, United States
- Ralph Salloum
- The Division of Hematology/Oncology, and Bone Marrow Transplantation, Nationwide Children’s Hospital and The Ohio State University, Columbus, OH, United States
- Maryam Fouladi
- Department of Pediatrics, The Ohio State University, Columbus, OH, United States
- Maryam Fouladi
- The Division of Hematology/Oncology, and Bone Marrow Transplantation, Nationwide Children’s Hospital and The Ohio State University, Columbus, OH, United States
- Daniel R. Boué
- Department of Pathology, The Ohio State University, Columbus, OH, United States
- Daniel R. Boué
- Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
- Elaine R. Mardis
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
- Elaine R. Mardis
- Department of Pediatrics, The Ohio State University, Columbus, OH, United States
- Catherine E. Cottrell
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
- Catherine E. Cottrell
- Department of Pathology, The Ohio State University, Columbus, OH, United States
- Catherine E. Cottrell
- Department of Pediatrics, The Ohio State University, Columbus, OH, United States
- DOI
- https://doi.org/10.3389/fonc.2024.1453309
- Journal volume & issue
-
Vol. 14
Abstract
IntroductionIn the setting of pediatric and adolescent young adult cancer, increased access to genomic profiling has enhanced the detection of genetic variation associated with cancer predisposition, including germline syndromic conditions. Noonan syndrome (NS) is associated with the germline RAS pathway activating alterations and increased risk of cancer. Herein, we describe our comprehensive molecular profiling approach, the association of NS with glioma and glioneuronal tumors, and the clinical and histopathologic characteristics associated with the disease.MethodsWithin an institutional pediatric cancer cohort (n = 314), molecular profiling comprised of paired somatic disease–germline comparator exome analysis, RNA sequencing, and tumor classification by DNA methylation analysis was performed.ResultsThrough the implementation of paired analysis, this study identified 4 of 314 (1.3%) individuals who harbored a germline PTPN11 variant associated with NS, of which 3 individuals were diagnosed with a glioma or glioneuronal tumor. Furthermore, we extend this study through collaboration with a peer institution to identify two additional individuals with NS and a glioma or glioneuronal tumor. Notably, in three of five (60%) individuals, paired genomic profiling led to a previously unrecognized diagnosis of Noonan syndrome despite an average age of cancer diagnosis of 16.8 years. The study of the disease-involved tissue identified signaling pathway dysregulation through somatic alteration of genes involved in cellular proliferation, survival, and differentiation.DiscussionComparative pathologic findings are presented to enable an in-depth examination of disease characteristics. This comprehensive analysis highlights the association of gliomas and glioneuronal tumors with RASopathies and the potential therapeutic challenges and importantly demonstrates the utility of genomic profiling for the identification of germline cancer predisposition.
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