Frequency and Type of KRAS Mutations in Routine Diagnostic Analysis of Metastatic Colorectal Cancer
Aims: Mutation analysis of the KRAS oncogene is now established as a predictive biomarker in colorectal cancer (CRC). Large prospective clinical trials showed that only CRCs with wild type KRAS respond to anti-epidermal growth factor receptor (EGFR) treatment. Therefore the mutation analysis is mandatory before treatment and reliable benchmarks of the frequency and types of KRAS-mutations have to be established for a routine testing of large numbers of metastatic CRCs. Methods: 1018 cases (879 primary tumors, 139 metastases) of metastatic colorectal cancer patients were analyzed for KRAS mutational status of codons 12 and 13 of the KRAS gene by genomic sequencing in a routine setting. Results were analyzed separately for specimens deriving from primary tumors and metastases. Results: KRAS mutations in codons 12 and 13 were present in 39.3 % of all analyzed CRCs. The most frequent types of mutations were glycine to aspartate on codon 12 (p.G12D, 36.0 %), glycine to valine on codon 12 (pG12V, 21.80 %) and glycine to aspartate on codon 13 (p.G13D, 18.5 %). They account for 76.3 % of all mutations, and prevailed in primary tumors as well as distant metastases indicating a robustness of the KRAS mutational status during neoplastic dissemination. Conclusions: The frequency of KRAS mutations and the preponderance of three types of mutations in codon 12 and 13 in a large, unselected cohort of metastatic CRC confirm the previous data of small and selected CRC samples. Thus a mutation frequency of 40 % and a cluster of three mutation types (p.G12D, pG12V and p.G13D) in primaries and metastases can be defined as benchmarks for routine KRAS-analyses.