NRAS associated RASopathy and embryonal rhabdomyosarcoma

Abstract

RASopathies are a group of phenotypically overlapping disorders that arise from dysregulation of the RAS/MAPK pathway. These disorders include Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome, and neurofibromatosis-Type 1. While somatic mutations in the three human Ras genes (KRAS, HRAS, and NRAS) are a common finding in a variety of cancers, germline mutations in each of the these genes cause developmental RASopathy phenotypes with mutations in specific genes typically correlating with specific phenotypes. We present the case of a germline heterozygous NRAS mutation producing a severe phenotype involving embryonal rhabdomyosarcoma, severe intellectual disability, and numerous melanocytic nevi in addition to more typical manifestations of Noonan syndrome. Additionally, the specific p.G12R NRAS mutation in this case is a common somatic mutation in cancer cells, and analysis of previously reported NRAS-RASopathy cases suggests that mutations at traditionally oncogenic codons are associated with elevated cancer risk not present with mutations at other sites. K E Y W O R D SCostello, embryonal rhabdomyosarcoma, Noonan, NRAS, RASopathy

Oncogenic NRAS Accelerates Rhabdomyosarcoma Formation When Occurring within a Specific Time Frame during Tumor Development in Mice

“…This might be similar in humans with Noonan syndrome, which is caused by germline mutations in NRAS and which predisposes the patients to ERMS development. Thus, although mutations at the NRAS G12 codon have been discovered in patients with this syndrome, ERMS-prototypic oncNRAS mutations, such as the G12D mutation or Q61K mutations [10], have never been found [16][17][18].…”

The Clinical Landscape of NRAS-mutated Juvenile Myelomonocytic Leukemia-like Myeloproliferation Includes Children With Costello Syndrome

“…Gly12 variants have been previously reported in the germline of 2 patients, one with Costello syndrome 15 and another with Noonan syndrome. 16 In addition, NRAS Gly12Ser has been cataloged in the germline of several patients with a RASopathy in ClinVar. 17 Furthermore, the Gly12 residue in HRAS and KRAS genes is recognized by ClinGen's RASopathy Expert Panel as a mutational hotspot.…”

“…For case 3, nonhematopoietic tissue, such as cultured fibroblasts, was not available; however, the variant allele frequency of 49% by next-generation sequencing was highly suggestive of a germline origin. Gly12 variants have been previously reported in the germline of 2 patients, one with Costello syndrome15 and another with Noonan syndrome 16. In addition, NRAS Gly12Ser has been cataloged in the germline of several patients with a RASopathy in ClinVar 17.…”

Cancer incidence and surveillance strategies in individuals withRASopathies

“…An analysis of the German Childhood Cancer Registry showed an approximately eightfold increased cancer risk in patients with Noonan syndrome, of which there were three Noonan children with a germline PTPN11 variant and a solid tumor: one neuroblastoma, one pilocytic astrocytoma, and one dysembryoplastic neuroepithelial tumor (Kratz et al, 2015) (Figure 1). Furthermore, multiple literature cases exist describing individuals with Noonan syndrome and solid tumors including rhabdomyosarcoma, brain tumors, and neuroblastoma (Boonyawat, Charoenpitakchai, & Suwanpakdee, 2019; El‐Ayadi et al, 2019; Garavelli et al, 2015; Garren, Stephan, & Hogue, 2020; Harms et al, 2018; Hastings, Newbury‐Ecob, Ng, & Taylor, 2010; Jongmans et al, 2010; Jung et al, 2003; Khan, McDowell, Upadhyaya, & Fryer, 1995; Lopez‐Miranda, Westra, Yazdani, & Boechat, 1997; Rankin, Short, Turnpenny, Castle, & Hanemann, 2013; Sherman, Ali‐Nazir, Gonzales‐Gomez, Finlay, & Dhall, 2009). While these reports suggest a possible association, a definitive, quantitative analysis of solid tumor risk is still needed to understand its true incidence in Noonan syndrome.…”