• What is NRAS?
  • NRAS in Thyroid Cancer
  • 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.

Related Pathways

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. 2015. NRAS. My Cancer Genome https://www.padiracinnovation.org/content/disease/thyroid-cancer/nras/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

NRAS in Thyroid Cancer

RAS mutations (HRAS, NRAS and KRAS) are found in all epithelial thyroid malignancies. The frequency of NRAS mutations in thyroid carcinomas is 6% (COSMIC). While most non-thyroid cancers have mutations in KRAS codons 12 and 13, most thyroid tumors have been found to have mutations in NRAS codon 61 and HRAS codon 61 (Nikiforov 2011).

Several studies have found RAS mutations to be prevalent in follicular carcinomas, follicular variant papillary carcinomas and poorly differentiated thyroid carcinomas. Ras-mutated thyroid cancers are prone to distant metastases to lung and bone rather than to locoregional lymph node involvement.

RAS mutations are the second most common mutation detected in fine-needle aspiration (FNA) biopsy samples from thyroid nodules and have a 74–88% positive predictive value for malignancy (Bhaijee and Nikiforov 2011).

Of note, RAS point mutations are mutually exclusive with other thyroid mutations such as BRAF, RET/PTC, or TRK rearrangements (Kimura et al. 2003) in papillary thyroid cancers . In follicular carcinomas, RAS mutations are mutually exclusive with PAX8-PPARG rearrangements (Nikiforova et al. 2003).


Table 1. Frequencies of Specific Mutations.
Gene Exon Amino Acid Position Amino Acid Change Nucleotide Change Frequency Among NRAS-Mutated Thyroid Cancer (COSMIC)
NRAS 3 61 p.Q61K c.181C>A 13%
p.Q61R c.182A>G 77%

Contributors: Allan V. Espinosa, M.D., Jill Gilbert, M.D., James Fagin, M.D.

Suggested Citation: Espinosa, A., J. Gilbert, J. Fagin. 2015. NRAS in Thyroid Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/thyroid-cancer/nras/ (Updated February 17).

Last Updated: February 17, 2015

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