• What is NRAS?
  • NRAS in Melanoma
  • Clinical Trials

NRAS

Three different human RAS genes have been identified: KRAS (homologous to the oncogene from the Kirsten rat sarcoma virus), HRAS (homologous to the oncogene from the Harvey rat sarcoma virus), and NRAS (first isolated from a human neuroblastoma). The different RAS genes are highly homologous but functionally distinct; the degree of redundancy remains a topic of investigation (reviewed in Pylayeva-Gupta et al. 2011). RAS proteins are small GTPases which cycle between inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound forms. RAS proteins are central mediators downstream of growth factor receptor signaling and therefore are critical for cell proliferation, survival, and differentiation. RAS can activate several downstream effectors, including the PI3K-AKT-mTOR pathway, which is involved in cell survival, and the RAS-RAF-MEK-ERK pathway, which is involved in cell proliferation (Figure 1).

RAS has been implicated in the pathogenesis of several cancers. Activating mutations within the RAS gene result in constitutive activation of the RAS GTPase, even in the absence of growth factor signaling. The result is a sustained proliferation signal within the cell.

Specific RAS genes are recurrently mutated in different malignancies. NRAS mutations are particularly common in melanoma, hepatocellular carcinoma, myeloid leukemias, and thyroid carcinoma (for reviews see Karnoub and Weinberg 2008 and Schubbert, Shannon, and Bollag 2007).

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Figure 1.
Simplified schematic of RAS signaling pathways. Growth factor binding to receptor tyrosine kinases results in RAS activation. The letter "K" within the schema denotes the tyrosine kinase domain.

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2014. NRAS. My Cancer Genome http://www.mycancergenome.org/content/disease/melanoma/nras/?tab=0 (Updated August 6).

Last Updated: August 6, 2014

NRAS Mutations in Melanoma

Somatic mutations in NRAS have been found in ~13–25% of all malignant melanomas (Ball et al. 1994; Curtin et al. 2005; van 't Veer et al. 1989). In the majority of cases, these mutations are missense mutations which introduce an amino acid substitution at positions 12, 13, or 61. The result of these mutations is constitutive activation of NRAS signaling pathways. NRAS mutations are found in all melanoma subtypes, but may be slightly more common in melanomas derived from chronic sun-damaged (CSD) skin (Ball et al. 1994; van 't Veer et al. 1989). Currently, there are no direct anti-NRAS therapies available.

In the vast majority of cases, NRAS mutations are non-overlapping with other oncogenic mutations found in melanoma (e.g., BRAF mutations, KIT mutations, etc.).


Contributors: Christine M. Lovly, M.D., Ph.D., William Pao, M.D., Ph.D. (through April 2014), Jeff Sosman, M.D.

Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2012. NRAS Mutations in Melanoma. My Cancer Genome http://www.mycancergenome.org/content/disease/melanoma/nras/ (Updated October 8).

Last Updated: October 8, 2012

NRAS-Associated Melanoma Clinical Trials

Great effort was made to include all clinical trials relevant for this mutation. However, the completeness of this information cannot be guaranteed.

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