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. 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 review see 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.
Last Updated: June 5, 2012
KRAS mutations are found in approximately 40% of patients with Type I EOC tumors. In the majority of cases, these mutations are missense mutations which introduce an amino acid substitution at position 12, 13, or 61. The result of these mutations is constitutive activation of KRAS signaling pathways. The most common mutation is KRAS G12D c.35G>A (COSMIC).
The role of KRAS as either a prognostic or predictive factor in EOC is unknown at this time. In one study KRAS mutations were associated with poor prognosis in metastatic Type I tumors (Jones et al. 2012). Another study showed that low grade tumors with KRAS mutations had a better outcome (Wong et al. 2010). Currently, there are no direct anti-KRAS therapies available. However, patients with KRAS mutated ovarian tumors may benefit from treatment with MEK inhibitors (Nakayama et al. 2008).
Table 1. Frequency of Somatic Gene Mutations in Epithelial Ovarian Cancer (EOC)
|EOC Overall||Type I||Type II|
|Gene Mutation||Low Grade Serous||Clear Cell||Endometrioid||Mucinous||High Grade Serous|
|KRAS||14% (COSMIC)||33% (Singer et al. 2003; Nakayama et al. 2006)||<1–7% (Kuo et al. 2009; Singer et al. 2003)||<1% (Singer et al. 2003)||50–75% (Gemignani et al. 2003)||<1% (TCGA 2011)|
Table 2. Frequencies of specific mutations.
|Gene||Exon||Amino Acid Position||Amino Acid Change||Nucleotide Change||Frequency Among KRAS-mutated Ovarian Cancer|
Last Updated: December 14, 2012
|Location of mutation||Codon 12|
|Frequency of KRAS mutations in ovarian cancer||14% (COSMIC)|
|Frequency of G12C mutations in KRAS-mutated ovarian cancer||4.8% (COSMIC)|
|Implications for Targeted Therapeutics|
|Response to erlotinib/gefitinib (EGFR TKIs)||Unknown at this time (Haldar et al. 2007)|
|Response to cetuximab, panitumumab (anti-EGFR antibodies)||Unknown at this time (Haldar et al. 2007)|
|Response to MEK inhibitors||Unknown at this time (Nakayama et al. 2008)|
The G12C mutation results in an amino acid substitution at position 12 in KRAS, from a glycine (G) to an cysteine (C).
Last Updated: December 14, 2012
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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