Nras

NRAS is an enzyme that is encoded by the NRAS gene in humans. NRAS was initially discovered in human neuroblastoma cells (NRAS= abbreviation for "Neuroblastoma RAS"). N-RAS oncogene is a member of the RAS gene family which includes KRAS, HRAS and the inactive pseudogenes c-HRAS2, c-KRAS1 and c-N-RAS. The N-RAS gene is located on chromosome 1.

N-RAS has GTP/GDP binding and GTPase activity and functions as a G-like regulatory protein and is involved in the normal control of cell growth. Activating mutations in the NRAS gene lead to a stabilization of NRAS in GTP-bound form. GTP binding leads to a permanent activation of BRAF and PI3K (phosphoinositide-3-kinase). PI3K posphorilises phosphatidylinositol to phosphatidylinositol-triphosphate which in turn activates AKT. PI3K regulates cell survival, proliferation, and growth.

In oncology, the determination of NRAS mutation status is important in the treatment of patients with colon carcinoma and malignant melanoma, among others. Furthermore, NRAS mutations are also occasionally found in lung carcinoma (about 1%).

In malignant melanoma, a mutated BRAF gene is detected in 40 to 50% of patients, a mutated NRAS gene in 15 to 20%, and a mutated KIT gene in 2-5%. These mutations are usually exclusive, meaning that either a BRAF mutation, NRAS mutation, or KIT mutation is found in a tumor. 2 BRAF inhibitors that inhibit mutant BRAF are approved for monotherapy of metastatic melanoma: vemurafenib and dabrafenib. These agents can achieve response rates of 50-60% in BRAF-mutated patients, with median survival extended up to 20 months. However, treatment success is often not durable.

An NRAS mutation analysis can be performed on paraffin-embedded tumor material.

1. Held L et al (2011) Oncogenetics of melanoma: Basis for molecular diagnostics. J Dtsch Dermatol Ges 9:510-517
2. Marshall CJ et al (1982) A transforming gene present in human sarcoma cell lines. Nature 299: 171-173.
3. Shimizu K et al. (1983) Isolation and preliminary characterization of the transforming gene of a human neuroblastoma cell line. PNAS 80: 383-387.