Kras

KRAS is the acronym for "Kirsten rat sarcoma viral oncogene". KRAS is the most common human driver oncogene, which, like HRAS and NRAS, belongs to the RAS oncogene family. KRAS encodes the KRAS protein of the same name. The KRAS protein is a monomeric polypeptide consisting of 189 amino acids. It transmits growth signals from theepidermal growth factor receptor(EGFR).

KRas thus acts as a central switch point in a number of signal transduction pathways involved in the regulation of cell growth and differentiation. This key position in the development of tumors made the KRas protein an important target in the development of oncological drugs. Mutations in the encoding KRAS gene result in a pathological gene product. The oncogene contributes to a permanent activation of this pathway and thus to carcinogenesis (see also under pertuzumab).

The molecular pathological determination of the KRAS mutation status plays an important role especially in metastatic colorectal carcinoma. Detection of a mutation in the KRAS oncogene is a negative predictor and predicts that treatment with an EGFR antagonist (e.g. pertuzumab) will be unsuccessful. Survival of patients without KRAS mutation is significantly higher than those KRAS mutated.

KRAS mutations in carcinomas of the gastrointestinal tract: In an analysis of KRAS status in patients with carcinomas of the gastrointestinal tract (n=17,900), KRAS mutations were found in varying frequencies. 7,559 tumors had a KRAS mutation, of which 325 (4.3%) had a G12C mutation and 7,234 (95.7%) had another KRAS mutation. The only baseline characteristic found to be associated with KRAS-G12C mutation was age: patients with a GI tumor with KRAS-G12C mutation were more likely to be < 60 years old than patients with another KRAS mutation (50% vs. 38.8%). A KRAS-G12C mutation was particularly common in malignancies of the appendix (3.9%), colorectal carcinomas (CRC 3.1%). Adenocarcinomas of the small intestine had a KRAS-G12C mutation in 1.4%, pancreatic carcinomas in 1.3%, and bile duct carcinomas in 1.2%. These mutations were even less common in gastric and liver malignancies and squamous cell carcinomas of the esophagus, and were not detected in any cases of adenocarcinomas of the esophagus and anal carcinomas in the cohort. A retrospective analysis from two Scandinavian cohort studies analyzed KRAS-G1C mutations in patients with CRC (colorectal cancer) and the effect on treatment outcome. In patients with KRAS-G12C mutation, the left colon was more frequently affected, peritoneal metastases appeared to be less frequent, and pulmonary metastases more frequent than in patients with other KRAS mutations. In the cohort studied, a KRAS-G12C mutation was not associated with worse overall survival (OS=overall survival) and progression-free survival (PFS=progression free survival) than other KRAS mutations.

In contrast, a retrospective study from Japan indicated prognostic relevance of the KRAS G12C mutation. It included data from 2,457 patients with metastatic CRC who had received first-line chemotherapy at one of four cancer centers in Japan from 2005 to 2017. 696 patients had a KRAS exon 2 mutation, of which 45 (6.5%) had a KRAS G12C mutation, and 651 (93.5%) had another KRAS mutation, most commonly G12D (n=261; 37.5%), G13D (n=160; 23.0%), or G12H (n=151; 21.7%). In multivariate analysis, the presence of a KRAS G12C mutation was associated with shorter PFS and OS than other KRAS mutations. The median PFS was 9.4 months with KRAS G12C mutation and 10.8 months with other KRAS mutation (hazard ratio [HR] 1.47; 95% confidence interval [CI] 1.06-2.01; p=0.015), and the median OS was 21.1 months with KRAS G12C mutation and 27.3 months with other KRAS mutation (HR 1.50; 95% CI 1.08-2.08; p=0.015).

Current evidence indicates that KRAS-G12C mutation has no prognostic significance in non-metastatic CRC, but is associated with worse prognosis in recurrence and metastatic setting.

Mutations in the KRAS gene are responsible for physical malformations (including short stature, facial anomalies, heart malformations), known as Noonan syndrome and as CFC syndrome(cardio-facio-cutaneous syndrome). Other mutations increase the risk of cancer.

Postzygotic mutations in the HRAS gene (95% of cases) and less frequently in the KRAS gene (5%) are present in nevus sebaceus.

Postzygotic HRAS mutations are also detected in phacomatosis pigmentokeratotica.

1. Groesser L et al (2012) Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome.Nat Genet 44:783-787.

2. Groesser L et al (2013) Phacomatosis pigmentokeratotica is caused by a postzygotic HRAS mutation in a multipotent progenitor cell. J Invest Dermatol 133:1998-2003.

3. Roth AD et al. (2010) Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol 28:466-474

4. Scott A et al (2020) The Impact of KRAS Mutation on the Presentation and Prognosis of Non-Metastatic Colon Cancer: an Analysis from the National Cancer Database. J Gastrointest Surg 24:1402-1410.