KRAS mutational status is known to be both a prognostic and predictive biomarker in patients with colorectal cancer. Specifically, mutations in ‘hotspot’ codons of the KRAS gene are associated with more aggressive disease in these individuals and with a poor response to EGFR inhibitors. However, recent work from Gillian Smith and colleagues might increase the clinical utility of this biomarker, as the authors have identified additional KRAS mutations that they recommend for inclusion in routine screening of KRAS mutational status in these patients. “We realized that there has been no systematic assessment of KRAS mutation burden outwith the hotspot codons, so we decided to screen the entire KRAS gene for mutations in a cohort of patients with colorectal cancer,” explains Smith.

The researchers screened the KRAS gene in 106 colorectal tumors and identified four additional KRAS mutations (Leu19Phe, Lys117Asn, Ala146Thr and Arg164Gln), which were verified to be tumor-specific as they were not detected in genomic DNA from matched blood samples. The investigators noted that the Lys117Asn and Ala146Thr mutations conferred similar phenotypes in vitro to those mediated by mutations in the ‘hotspot’ codons 12, 13 and 61 (albeit with variable gene-expression profiles), indicating the potential ability of these additional mutations to alter the phenotype of patients with colorectal cancer, and therefore their response to chemotherapy.

Furthermore, the Ala146Thr mutation was found in 6.5% of tumors, none of which had additional KRAS mutations in the ‘hotspot’ codons, and the authors stress that current screening protocols are therefore unable to detect all significant KRAS mutations. “Our data suggest that current mutation screening strategies underestimate the KRAS mutation frequency in colorectal tumors by approximately one third,” says Smith. “We therefore suggest that routine mutation screening in patients with colorectal cancer is extended beyond previously described mutational hotspots”.

In recent times, personalized medicine is receiving increased interest and resources. Accordingly, the researchers next plan to investigate the extent to which individual KRAS mutations influence response to EGFR inhibitors, such as cetuximab. “Future personalized patient treatments will be decided on the basis of both patient and tumor genotype and phenotype. The need to stratify the treatment of colorectal cancer with chemotherapy, based on whether or not KRAS mutations are present, exemplifies this,” concludes Roland Wolf, the study’s principal investigator.

Rowan Higgs