Neurofibromatosis type 1 (NF-1) is the most common cancer predisposition syndrome associated with central nervous system (CNS) cancers. Although other non-NF-1 RASopathies, including Noonan syndrome are as prevalent a NF-1, their association with CNS cancers has been uncommonly reported. The phenotype associated with Noonan syndrome varies within a wide spectrum of clinical severity and depending on age and genotype. Clinical characteristics of non-NF-1 RASopathies and NF-1 can also overlap. Germline mutations reported in non-NF-1 RASopathies overlap with the somatic mutations found in several pediatric CNS cancers, particularly low-grade gliomas (LGGs). Since non-NF-1 RASopathies can be often overlooked or misdiagnosed, we postulate that their association with CNS cancers is more common than currently recognized. We assume that most identified subjects will have significant clinical manifestations associated with their RASopathy. We also hypothesize that the molecular abnormalities in CNS cancers in subjects with non-NF-1 RASopathies will be distinct from non-affected patients and that they may influence the tumor response to new biologic anticancer agents. Finally, we believe that non-NF-1 RASopathies may account for a small but clinically significant share of specific CNS cancers (e.g., LGGs).
What are the goals of this project?
We started this multi-institutional prospective study in the US to evaluate clinical and radiologic characteristics, and to perform detailed molecular analyses in germline and tumor samples from patients with non-NF-1 RASopathies and CNS cancers. Clinical data including type of RASopathy and CNS cancer, demographics, and anticancer treatment information will be gathered. Pertinent imaging studies of CNS cancers will be centrally reviewed. We plan to perform detailed molecular analyses of available tumors and germline samples consisting of whole-exome and RNA sequencing.
What is the impact of this project?
This research will raise awareness of the role of these relatively common autosomal disorders in the predisposition to pediatric CNS cancers and to potentially identify better “actionable” molecular targets in the tumors of affected patients.
Why the CBTN request is important to this project?
We are collecting cases of the association of non-NF-1 RASopathies and CNS cancers at our institution and from other institutions in the US. By using data from cases collected through CBTN, we are hoping to increase the size of our cohort of research participants
The Children's Brain Tumor Network contributed to this project by providing access to the Pediatric Brain Tumor Atlas.