Noonan Syndrome with PTPN11 Mutations Elevates Risk for Multifocal Low-Grade CNS Tumors

Overview

This multi-institutional study of 24 patients with Noonan syndrome (NS) reveals a significant association between germline PTPN11 mutations and the development of multifocal low-grade central nervous system (CNS) tumors featuring somatic FGFR1 alterations. The findings highlight novel clinical, radiological, and molecular characteristics that may guide targeted therapies.

Background

Cancer predisposition syndromes contribute to 8%–21% of pediatric CNS cancers, with RASopathies such as Noonan syndrome being common non-NF1 germline disorders linked to tumorigenesis. NS occurs in up to 1 in 1,000 live births and has been sporadically associated with low-grade gliomas. Prior to this study, large-scale clinical and molecular characterization of CNS tumors in NS patients was lacking. This study leverages a large cohort to elucidate the interplay between germline PTPN11 mutations and somatic FGFR1 alterations in CNS tumor development.

Data Highlights

Twenty-four patients with NNFRAS and CNS tumors were enrolled, with 79% male and 22 patients under 18 years at diagnosis. Whole exome and RNA sequencing were performed on germline and tumor samples, achieving an average target depth of 100X. DNA methylation profiling was conducted using the Illumina MethylationEPIC BeadChip, and CNS tumor methylation classifier scores were used for diagnosis. Statistical correlation analyses compared genotype and tumor occurrence with published data at 95% confidence intervals.

Key Findings

• Germline PTPN11 mutations in NS patients are strongly associated with multifocal low-grade CNS tumors.
• Somatic FGFR1 alterations frequently co-occur with PTPN11 mutations in these tumors, suggesting a molecular interaction driving tumorigenesis.
• Multifocal tumor involvement is a consistent radiological feature in NS-associated CNS tumors.
• DNA methylation profiling supports the classification of these tumors within low-grade glioma categories.
• The study provides the largest cohort to date characterizing clinical, radiological, and molecular features of NS-related CNS tumors.

Clinical Implications

Recognition of the association between PTPN11 germline mutations and FGFR1 somatic alterations in NS patients can inform surveillance strategies for early tumor detection. Molecular profiling of tumors may identify candidates for FGFR1-targeted therapies, potentially improving outcomes. Multidisciplinary management including genetic counseling is essential for this population.

Conclusion

This study establishes a novel link between Noonan syndrome with PTPN11 mutations and multifocal low-grade CNS tumors harboring FGFR1 alterations, expanding understanding of tumorigenesis in RASopathies and opening avenues for targeted treatment approaches.

References

1. Introduction and Methods -- Noonan Syndrome Associated with PTPN11 Mutations Increases Risk for Multifocal Low-Grade CNS Tumors Featuring FGFR1 Alterations