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KRAS - Gene Mutation Analysis

Key Facts 

• KRAS is an important signalling intermediate in the EGFR pathway
• Three activating mutations are known to occur, at codons 12,,13, and 61
• KRAS mutations are relatively common in colorectal and lung cancers
• The presence of a KRAS mutation suggests a patient is unlikely to respond to EGFR-targeted treatment

In different cancer types, in particular those of colorectum and lung, certain subsets of patients have been shown to benefit from anti-EGFR therapies; however a significant proportion show no benefit from these agents. The KRAS gene encodes a protein that plays a key role in transmitting the original signal from EGFR downstream to activate important cell functions, in particular proliferation and survival.

Acquired mutations of this gene commonly occur in pancreatic, colorectal and lung tumours. These mutations are activating, leading to uncontrolled signalling. They occur primarily in one small region of the gene and make tumours resistant to anti-EGFR therapies. Patients with such mutations in their tumours are therefore considered unlikely to benefit from anti-EGFR therapies. Current guidelines in the US and Europe suggest that all patients being considered for such therapies should be tested for KRAS mutations.

Source BioScience offers KRAS mutation testing based on two alternative CE-marked technologies, both suitable for archival FFPE tissue samples:

•  The Qiagen Therascreen™ KRAS Mutation Test uses real-time PCR to detect the 7 most common activating mutations found in the KRAS gene
• Pyrosequencing using the Qiagen/Biotage PyroMark™ KRAS Test provides an alternative technique for evaluating the same 7 mutations

These mutations, all located in exon 2, are associated with resistance to the anti-EGFR monoclonal antibody therapeutics cetuximab (Erbitux™) and panitumumab (Vectibix™), and the small molecule inhibitors of EGFR gefitinib (Iressa™) and erlotinib (Tarceva™). The results of mutation tests are reported as positive or negative for the presence of a particular mutation, along with additional information about relative frequencies of particular mutations in colorectal and lung tumours.

References:

National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology for Colon and Rectal Cancer. Published online November 2008. http://www.nccn.org/about/news/newsinfo.asp?NewsID=194

van Krieken et al. (2008) KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program. Virchows Arch 453:417