Integrated tumor and germline whole-exome sequencing identifies mutations in MAPK and PI3K pathway genes in an adolescent with rosette-forming glioneuronal tumor of the fourth ventricle

Frank Y Lin; Katie Bergstrom; Richard Person; Abhishek Bavle; Leomar Y Ballester; Sarah Scollon; Robin Raesz-Martinez; Andrew Jea; Sherri Birchansky; David A Wheeler; Stacey L Berg; Murali M Chintagumpala; Adekunle M Adesina; Christine Eng; Angshumoy Roy; Sharon E Plon; D Williams Parsons

doi:10.1101/mcs.a001057

Integrated tumor and germline whole-exome sequencing identifies mutations in MAPK and PI3K pathway genes in an adolescent with rosette-forming glioneuronal tumor of the fourth ventricle

Cold Spring Harb Mol Case Stud. 2016 Sep;2(5):a001057. doi: 10.1101/mcs.a001057.

Authors

Frank Y Lin¹, Katie Bergstrom², Richard Person³, Abhishek Bavle², Leomar Y Ballester⁴, Sarah Scollon², Robin Raesz-Martinez², Andrew Jea⁵, Sherri Birchansky⁶, David A Wheeler⁷, Stacey L Berg¹, Murali M Chintagumpala¹, Adekunle M Adesina⁸, Christine Eng³, Angshumoy Roy⁹, Sharon E Plon¹⁰, D Williams Parsons¹⁰

Affiliations

¹ Texas Children's Cancer Center and the Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030, USA;; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA;
² Texas Children's Cancer Center and the Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030, USA;
³ Department of Molecular and Human Genetics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030, USA;
⁴ Department of Pathology, Texas Children's Hospital Baylor College of Medicine, Houston, Texas 77030, USA;
⁵ Division of Pediatric Neurosurgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030, USA;
⁶ Department of Pediatric Radiology, Texas Children's Hospital Baylor College of Medicine, Houston, Texas 77030, USA;
⁷ Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA;; Department of Molecular and Human Genetics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030, USA;; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
⁸ Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA;; Department of Pathology, Texas Children's Hospital Baylor College of Medicine, Houston, Texas 77030, USA;
⁹ Texas Children's Cancer Center and the Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030, USA;; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA;; Department of Pathology, Texas Children's Hospital Baylor College of Medicine, Houston, Texas 77030, USA;
¹⁰ Texas Children's Cancer Center and the Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030, USA;; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA;; Department of Molecular and Human Genetics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030, USA;; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.

Abstract

The integration of genome-scale studies such as whole-exome sequencing (WES) into the clinical care of children with cancer has the potential to provide insight into the genetic basis of an individual's cancer with implications for clinical management. This report describes the results of clinical tumor and germline WES for a patient with a rare tumor diagnosis, rosette-forming glioneuronal tumor of the fourth ventricle (RGNT). Three pathogenic gene alterations with implications for clinical care were identified: somatic activating hotspot mutations in FGFR1 (p.N546K) and PIK3CA (p.H1047R) and a germline pathogenic variant in PTPN11 (p.N308S) diagnostic for Noonan syndrome. The molecular landscape of RGNT is not well-described, but these data are consistent with prior observations regarding the importance of the interconnected MAPK and PI3K/AKT/mTOR signaling pathways in this rare tumor. The co-occurrence of FGFR1, PIK3CA, and PTPN11 alterations provides further evidence for consideration of RGNT as a distinct molecular entity from pediatric low-grade gliomas and suggests potential therapeutic strategies for this patient in the event of tumor recurrence as novel agents targeting these pathways enter pediatric clinical trials. Although RGNT has not been definitively linked with cancer predisposition syndromes, two prior cases have been reported in patients with RASopathies (Noonan syndrome and neurofibromatosis type 1 [NF1]), providing an additional link between these tumors and the mitogen-activated protein kinase (MAPK) signaling pathway. In summary, this case provides an example of the potential for genome-scale sequencing technologies to provide insight into the biology of rare tumors and yield both tumor and germline results of potential relevance to patient care.

Keywords: neoplasm of the central nervous system.