NRAS gene

The NRAS gene (NRAS stands for: Neuroblastoma RAS Viral Oncogene) is a protein-coding gene located on chromosome 1p13.2. Related pathways include prolactin signaling and downstream signaling of activated FGFR2. Gene Ontology annotations for this gene include GTP binding and binding to a proteinaceous complex. An important paralog of this gene is HRAS.

It is an NRAS oncogene that codes for a membrane protein (see below). which shuttles back and forth between the Golgi apparatus and the plasma membrane. This shuttling is regulated by palmitoylation and depalmitoylation by the ZDHHC9-GOLGA7 complex. The encoded NRAS protein, which has intrinsic GTPase activity, is activated by a guanine nucleotide exchange factor and inactivated by a GTPase-activating protein.

Mutations in the RAS protein family have been frequently observed in various types of cancer. The amino acid positions G12, G13 and Q61 are responsible for the vast majority of these mutations. The isoforms, despite their gross similarity, also behave very differently when expressed in non-native tissue types, likely due to differences in the C-terminal hyper-variable regions. Although these RAS mutants are very common in cancer, targeting these mutants has been very difficult to achieve and has not yet become common in the clinic.

Mutations in the RAS gene have been associated with rectal cancer, follicular thyroid cancer, autoimmune lymphoproliferative syndrome, Noonan syndrome and juvenile myelomonocytic leukemia and melanoma. Neurocutaneous melanosis is caused by an early embryonic NRAS mutation in the neuroectoderm.

Clinic of RAS mosaics:

If RAS mutations occur earlier in the somatic development of an organism, several tissues may be affected. This results in syndromic clinical pictures. One example is Schimmelpenning-Feuerstein-Mims syndrome (SFMS), in which the CNS, eyes and skeleton (osteomalacia, hypophosphatemic rickets) can be particularly affected, with evidence of mosaic mutations in HRAS, KRAS and NRAS. The considerable variability of the clinical symptoms can be explained by the identification as a mosaic disease. Syndromes with congenital abnormalities of the eye and skin have also been identified as mosaic RASopathy: oculo-ectodermal syndrome (OES, mutations in KRAS). The main features are epibulbar dermoids and congenital defects of the scalp.

Other examples include encephalo-cranio-cutaneous lipomatosis (ECCL, mutations in FGFR1 and KRAS), in which the eponymous lipomas are also present in the CNS. Both syndromes can have other skin abnormalities, including a nevus sebaceus. They also include a predisposition to jaw tumors, non-ossifying fibromas and, in the case of ECCL, low-grade gliomas.

As it is not always possible to clearly assign previously used clinical diagnoses, the term (KRAS-associated) mosaic RASopathy is often more appropriate.

Around a quarter of melanoma patients carry activating NRAS mutations, which makes the treatment of this malignant disease particularly challenging. Patients with NRAS mutations have an overall poorer prognosis due to the high aggressiveness of RAS mutation tumors, the lack of efficient targeted therapies or the rapid emergence of resistance to existing treatments. NRAS melanomas experience both intrinsic and acquired resistance when treated with single or combined targeted therapies involving MAPK and CDK4/6 inhibitors and/or checkpoint inhibitory immunotherapy (Randic T et al. 2021/ Thomas NE et al. 2015).

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