Abstract IA16: RASopathies: the other face of RAS signaling upregulation
Authors: Tartaglia Marco 
Published: May 2023

Abstract
RAS proteins control a major intracellular signaling network that, depending on the cellular context, mediates response to external stimuli to control diverse biological functions. Within this network, signal flow through the RAF-MEK-ERK (MAPK, hereafter) pathway, modulates a wide array of cellular processes as well as early and late developmental programs. Signaling through the RAS-MAPK cascade is tightly controlled, and its enhanced activation has been known for decades to represent a major event in oncogenesis. Unexpectedly, discoveries derived from a massive disease gene hunting effort have more recently established a picture in which the upregulation of this signaling cascade underlies a group of clinically related developmental disorders collectively known as “RASopathies”, which share cardiac defects, reduced postnatal growth, variable cognitive deficits, facial dysmorphism, ectodermal and musculoskeletal anomalies, and variably increased risk for certain malignancies as major features. Based on the relatively high prevalence of some of these disorders (i.e., Noonan syndrome and neurofibromatosis type 1), the dysregulation of this signaling pathway represents one of the most common events affecting development. RASopathies are caused by mutations in genes encoding RAS proteins and structurally/functionally related GTPases, regulators of RAS function, modulators of RAS interaction with effectors or downstream signal transducers of the MAPK backbone. A subset of these genes have previously been implicated in cancer. Many of these RASopathy-causing alleles encode proteins with upregulated functional behavior, but with less activating strength compared to those contributing to oncogenesis. In these genes, a largely non-overlapping spectrum of germline and somatic mutations is generally observed. On the other hand, a few disorders result from a protein with defective function. In these, the implicated proteins negatively control signal flow, and the pathogenic event contributing to oncogenesis is generally represented by a second somatic hit involving the retained wild-type allele. The understanding of the molecular mechanisms involved in the pathogenesis of RASopathies has provided novel and relevant insights in cancer research. The identification of PTPN11 as major disease gene underlying Noonan syndrome represented the basis for the discovery that SHP2, the protein encoded by PTPN11, functions as an oncoprotein in childhood hematologic malignancies when mutated. More recently, genomic sequencing of RASopathies has allowed to identify circuits and players with previously unrecognized regulatory role on RAS function and signaling through the MAPK cascade. Here is provided an overview on the genes implicated in this group of developmental disorders, the molecular basis underlying the differential impact of germline and somatic mutations in development and cancer, the unanticipated molecular mechanisms converging toward the dysregulation of this signaling cascade, and major clinically relevant genotype-phenotype correlations.
Citation Format: Marco Tartaglia. RASopathies: the other face of RAS signaling upregulation [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA16.