Solid Tumors in RASopathies: Insights from a Large Monocentric Cohort and Systematic Review of the Literature

Background. The RAS-MAPK signaling cascade mediates cellular responses to external stimuli, regulating key processes involved in tumorigenesis, including growth, differentiation, and survival. RASopathies are a group of neurodevelopmental disorders caused by dysregulated RAS-MAPK activity and characterized by overlapping clinical presentations. While individuals with Neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and CBL-associated syndrome have an established increased cancer risk, data regarding tumor predisposition in other RASopathies remain anecdotal. Methods. We investigated the prevalence and spectrum of solid tumors in NS and related RASopathies, excluding NF1, through a retrospective analysis of a large monocentric cohort. These findings were complemented with data from an updated systematic review of the literature. Results. This study reports the largest single-center cohort of individuals with RASopathies monitored for solid tumors to date (n = 138; age range, 2–48 years). Solid neoplasms were identified in 10.8% of individuals with NS, 47.8% with CS, and 7.3% with cardiofaciocutaneous syndrome (CFCS). Multiple tumors occurred in 41.6% of CS patients, and one CFCS patient developed relapsing neoplasia. Tumor onset occurred at a younger age compared with the general population, particularly in individuals with CS. Distinct tumor spectra were observed among NS patients carrying PTPN11 and SOS1 pathogenic variants. Moreover, we identified a subset of potentially high-risk variants in RASopathy-causing genes that may confer increased susceptibility to solid tumors. Conclusion. Our findings provide clinically relevant insights into tumor predisposition across RASopathies and underscore the need for tailored surveillance strategies and evidence-based clinical guidelines for each disorder.