Solid tumours in RASopathies: insights from a large monocentric cohort and systematic review of the literature.

PTPN11, HRAS, SOS1

Dysregulation of the RAS-MAPK pathway with a solid tumour risk that depends on the syndrome and the genotype: bladder tumours in Costello syndrome, low-grade central nervous system tumours in Noonan syndrome, particularly in carriers of PTPN11 variants

Dysregulation of the RAS-mitogen-activated protein kinase signalling pathway underlies RASopathies, a family of neurodevelopmental disorders associated with variable cancer predisposition, but the prevalence and spectrum of solid tumours and the contribution of specific variants to tumour susceptibility remain poorly defined. The authors assessed solid tumour prevalence and spectrum in the largest single-centre cohort of individuals with RASopathies (n = 138), excluding neurofibromatosis type 1, and integrated these findings with a systematic literature review to examine tumour distribution and genotype-phenotype correlations. At least one solid tumour is identified in 10.8% of individuals with Noonan syndrome (NS), 47.8% of those with Costello syndrome (CS) and 7.3% of those with cardiofaciocutaneous syndrome (CFCS), with a malignant tumour in 5.4%, 30.4% and 2.4% of them respectively; Costello syndrome shows the highest tumour burden, frequently with multiple primary tumours, predominantly of the bladder, whereas low-grade central nervous system tumours predominate in Noonan syndrome, particularly in carriers of PTPN11 variants. Median age at onset is 19, 14 and 13 years in NS, CS and CFCS respectively, and the literature analysis identifies candidate variants in HRAS, PTPN11 and SOS1 associated with an increased risk of solid tumours, differing from the mutational hotspots reported in childhood leukaemia or sporadic cancers.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The contrast between the 47.8% of individuals with at least one solid tumour in Costello syndrome (30.4% with a malignant tumour), mostly of the bladder, and the 7.3% in cardiofaciocutaneous syndrome is marked enough to guide the content of syndrome-specific surveillance, which the authors word conditionally. The reservations are classic but important: monocentric recruitment liable to overestimate prevalences, sample sizes per syndrome and confidence intervals absent from the abstract, and candidate variants drawn from a literature exposed to publication bias. Since the HRAS, PTPN11 and SOS1 variants associated with solid tumours differ from the hotspots of leukaemias and sporadic cancers, what is known about these genes in somatic oncology should not be transposed to them directly.

Analysis by Dr Thibaut Benquey