KRAS
KRAS protein has an important role in cell signalling. KRAS is situated inside the cell, where it is usually tethered to the cell membrane, close to the intracellular parts of certain receptors on the cell surface.
KRAS protein acts as an on/off switch for downstream signalling of these receptors inside the cell. Factors that trigger signalling pathways mediated by KRAS include Epidermal Growth Factor (EGF), which binds to Epidermal Growth Factor Receptor (EGFR) and activates it. This activation, mediated by KRAS, may have various effects for the cell, including cell proliferation.
KRAS mutations
The human KRAS protein is encoded by the KRAS gene. When the gene is not mutated, the protein functions normally. However, certain mutations in the KRAS gene result in the expression of KRAS protein that is constitutively active. This causes uncontrolled cell growth and proliferation – a hallmark of a cancer cell. Such KRAS gene mutations are often found in e.g. colorectal, pancreatic and lung cancer tumours, and are thus called oncogenic (cancer-causing).
Indeed, the oncogenic, mutated versions of KRAS explain the name of the protein: V-Ki-Ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). In cancer, oncogenic KRAS mutations are most often found only in the tumour and are not inherited.
KRAS and EGFR inhibitor drugs
Some anti-cancer drugs target the EGFR pathway to block EGFR signalling, and thereby to block tumour growth and proliferation. These therapeutics include Panitumumab (Vectibix®, Amgen) and Cetuximab (Erbitux®, Merck Serono) for colorectal cancer, which act by inhibiting EGFR activation.
However, if the tumour has mutated and thus oncogenic, constitutively active KRAS, which acts as a downstream signalling mediator from EGFR, Panitumumab and Cetuximab will not work.
KRAS mutation testing in colorectal cancer
Approximately 40% of colorectal cancers have mutated KRAS. In order to ensure that anti-EGFR therapeutics are not prescribed to colorectal cancer patients who will not benefit, KRAS mutation testing is required before commencing Panitumumab or Cetuximab therapy.
The KRAS mutation test provided by Lab21 detects oncogenic KRAS mutations with high sensitivity and specificity. Our test turnaround time is only 5 working days.
KRAS mutation testing for colorectal cancer is funded by pharmaceutical companies for certain patients. More information is available from Lab21 Customer Services.
BRAF and KRAS mutation testing
BRAF is another important protein involved in the EGFR signalling pathway where it acts downstream from KRAS.
Mutated BRAF gene is associated with poor prognosis and poor response to anti-EGFR therapeutics in colorectal cancer. BRAF mutation testing is available from Lab21, and is easily combined with KRAS mutation testing.
References- Fakih MM. (2010). KRAS mutation screening in colorectal cancer: From paper to practice. Clin Colorectal Cancer 2010; 9(1): 22-30.
- Massarelli et al. KRAS Mutation Is an Important Predictor of Resistance to Therapy with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer. Clin Cancer Res, 2007; 13 (10).
- Pao et al. KRAS mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib. PloS Medicine, 2005; 2(1): 57-61.
- Eberhard et al. Mutations in the EGFR and in K-RAS are predictive and prognostic indicators in patients with NSCLC treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol, 2005; 23: 5900-5909.
- Toschi and Cappuzzo. Understanding the new genetics of responsiveness to EGFR tyrosine kinase inhibitors. Oncologist 12, 2007; 211-220.
- Han et al. Optimization of Patient Selection for Gefitinib in Non-Small Cell Lung Cancer by combined analysis of Epidermal Growth Factor Receptor Mutation, K-RAS Mutation, and AKT Phosphorylation. Clin Cancer Res, 2006; 12(8):2538-2544.
- Newton et al. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS) Nucleic Acids Res, 1989; 17 (7): 2503-16.
- Lievre et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol, 2008; 26: 374-379.
- Yen et al. Activating KRAS mutations and overexpression of epidermal growth factor receptor as independent predictors on metastatic colorectal cancer patients treated with Cetuximab. Ann Surg, 2009, published ahead of print.
- NICE Technology Appraisal TA176 Colorectal cancer (first line) – cetuximab: full guideline, 26th August 2009.
KRAS testing process
To request KRAS mutation testing, the first point of contact is the dedicated Lab21 Customer Services Team who handle:
- Test Requests and Customer Support
- Liaison with Sample Retention Sites for sample retrieval
- Reporting of the Results
KRAS mutation test requires sections from a formalin-fixed paraffin embedded (FFPE) tumour sample, from which DNA is extracted. This DNA is then used for detection of KRAS mutations by a CE-Marked PCR assay that detects the 7 key KRAS mutations with high sensitivity of 1%.
Test turnaround time is 5 working days from the receipt of the sample at Lab21.
KRAS mutation testing for colorectal cancer is funded by pharmaceutical companies for certain patients. More information is available from Lab21 Customer Services.
Please note that special pricing for the BRAF mutation test may be available when BRAF Mutation Test is requested together with a KRAS mutation test. BRAF and KRAS tests can be performed from the same sample.
KRAS Mutation Test from Lab21
KRAS Customer ServicesPhone:0845 6777199 (UK)
+44 (0)1223 395450 (Intl)Email:kras@lab21.com