• What is NRAS?
  • NRAS in Colorectal Cancer
  • NRAS No Mutation Detected
  • Clinical Trials


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).


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/colorectal-cancer/nras/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

NRAS in Colorectal Cancer

NRAS mutations occur in ~1–6% of colorectal cancers (COSMIC; De Roock et al. 2010; Irahara et al. 2009; Janku et al. 2007; Vaughn et al. 2011).

Wild type NRAS, together with wild type BRAF and KRAS, is associated response to EGFR antibody therapy (De Mattos-Arruda, Dienstmann, and Tabernero 2011; De Roock et al. 2010).

Several studies have shown that patients with NRAS-mutated tumors are less likely to respond to cetuximab or panitumumab, but this may not have an effect on PFS or overall survival (De Mattos-Arruda, Dienstmann, and Tabernero 2011; De Roock et al. 2010; Peeters et al. 2010).​

Contributors: Emily Chan, M.D., Ph.D.

Suggested Citation: Chan, E. 2015. NRAS in Colorectal Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/colorectal-cancer/nras/ (Updated June 18).

Last Updated: June 18, 2015

No KRAS and No NRAS Mutation Detected in Colorectal Cancer

Location of mutation N/A
Frequency of no KRAS or NRAS mutation detected in colorectal cancer 50% (Douillard et al. 2013)
Implications for Targeted Therapeutics
Response to erlotinib/gefitinib (EGFR TKIs) Unknown at this timea
Response to cetuximab/panitumumab (anti-EGFR antibodies) Confers increased sensitivityb

Approximately 50% of all colorectal cancers have no mutations detected in exons 2, 3, or 4 of RAS genes KRAS or NRAS. While the FDA currently recommends the use of EGFR antibody therapy only in colon cancers wild type at codons 12 and 13 of KRAS, more recent data shows that EGFR antibody therapy is unlikely to be beneficial in tumors with any KRAS or NRAS mutations. Based on this data, the NCCN updated their guidelines to recommend testing metastatic colorectal cancers for mutations in both KRAS and NRAS; previous standard of care was to test only exon 2 of KRAS (NCCN 2014). The EMEA requires testing of KRAS and NRAS eons 2, 3, and 4 for use of cetuximab (2014a) and panitumumab (2014b).

Of note, KRAS or NRAS "no mutation detected" means that tumors were tested for one or more KRAS or NRAS mutations and none were detected. KRAS or NRAS with no mutation detected is sometimes referred to as KRAS or NRAS "wild type." However, these two nomenclatures do not necessarily refer to the same thing. Strictly speaking, the mutation status should be qualified based on the testing method used. For example, if the testing only included amino acids G12, G13, and Q61 in KRAS, and no mutation was detected, then the KRAS mutation status for that tumor would be "wild type at amino acids G12, G13, and Q61."

a Gefitinib monotherapy is not active in metastatic colorectal cancer (Rothenberg et al. 2005).

b Prospective–retrospective analyses of the PRIME (Douillard et al. 2013), PEAK (Karthaus et al. 2013), OPUS (Tejpar et al. 2014), CRYSTAL (Ciardiello et al. 2014), FIRE-3 (Stintzing et al. 2014), and 20050181 (Peeters et al. 2014) clinical trials indicate that patients with tumors harboring KRAS and NRAS with no mutations detected in exons 2, 3, and 4 predict benefit from anti-EGFR antibody therapy given in combination with chemotherapy; benefits included increased progression-free survival and overall survival. In addition, patients with tumors harboring wild type KRAS may benefit from anti-EGFR antibody monotherapy (Amado et al. 2008). While KRAS and NRAS testing is not required by the FDA, testing is recommended by NCCN (2014) and is required by EMEA (2014a; 2014b).

Note that this page is cross-listed under KRAS no mutation detected in colorectal cancer.


Contributors: Emily Chan, M.D., Ph.D.

Suggested Citation: Chan, E. 2014. No KRAS and No NRAS Mutation Detected in Colorectal Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/colorectal-cancer/nras/316/ (Updated August 6).

Last Updated: August 6, 2014

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