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. KRAS mutations are particularly common in colon cancer, lung cancer, and pancreatic cancer (for reviews see Karnoub and Weinberg 2008 and Schubbert, Shannon, and Bollag 2007).
Figure 1. Schematic of the MAPK and PI3K pathways. Growth factor binding to receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2014. KRAS. My Cancer Genome http://www.mycancergenome.org/content/disease/colorectal-cancer/kras/?tab=0 (Updated August 6).
Last Updated: August 6, 2014
KRAS in Colorectal Cancer
Suggested Citation: Chan, E. 2015. KRAS in Colorectal Cancer. My Cancer Genome http://www.mycancergenome.org/content/disease/colorectal-cancer/kras/ (Updated June 18).
Last Updated: June 18, 2015
No KRAS and No NRAS Mutation Detected in Colorectal Cancer
|Location of mutation
|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 NRAS no mutation detected in colorectal cancer.
Suggested Citation: Chan, E. 2014. No KRAS and No NRAS Mutation Detected in Colorectal Cancer. My Cancer Genome http://www.mycancergenome.org/content/disease/colorectal-cancer/kras/44/ (Updated August 6).
Last Updated: August 6, 2014
KRAS-Associated Colorectal Cancer Clinical Trials
Great effort was made to include all clinical trials relevant for this mutation. However, the completeness of this information cannot be guaranteed.