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
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. 2015. KRAS. My Cancer
(Updated December 7).
Last Updated: December 7, 2015
KRAS in Colorectal Cancer
Suggested Citation: Chan, E. 2015. KRAS in Colorectal Cancer. My Cancer
(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
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.
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
(Updated August 6).
Last Updated: August 6, 2014
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