RASopathy Genes: Germline Risk and Somatic Cancers

RAS/MAPK signaling is one of the most critical in mammalian biology. Given this, hyperactivation of the RAS/MAPK pathway, via somatic mutation or germline pathogenic variants, is a frequent event in cancer and causative for RASopathies, respectively. Somatic mutations in one of the three isoforms of RAS, or downstream effector genes, are present in roughly one-third of all human cancers. Pancreatic cancer, a highly lethal cancer, is molecularly characterized by the presence of KRAS p.G12D in over 90% of all tumors and is known to initiate tumor development. A high percentage of melanomas are characterized by the presence of BRAF p.V600E, which also represents a successful therapeutic target. In contrast, pathogenic germline variants in RAS/MAPK genes underlie the RASopathies, where increased cancer risk has been observed in some, but not all, syndromes. In Costello syndrome, arising from germline HRAS pathogenic variants, cancer risk is observed in approximately 17% of individuals by age 20 years. However, in Legius syndrome, arising from SPRED1 variants, cancer risk is comparable to that of the general population. Understanding the intersections of RAS/MAPK somatic and germline variation may reveal novel strategies to inform clinical care in both RAS-related cancer and the RASopathies.