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

Original research paper: Smith, G. et al. Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumors—implications for personalised cancer medicine. Br. J. Cancer 102, 693–703 (2010)

CANCER Research UK scientists have discovered how arsenic works as an effective treatment for leukaemia – according to a report in Nature Cell Biology.

Patients with a certain kind of leukaemia – acute promyelocytic leukaemia – can be successfully treated with arsenic**, but scientists didn’t know how the process worked.

Now scientists have solved the mystery of how arsenic can treat cancer, more targeted treatments with fewer side effects are likely to be developed.

Lead author, Cancer Research UK’s Professor Ronald Hay based at the University of Dundee, said: “Our discovery is key to understanding how we can enhance the anti-cancer properties of this poison.”

“Knowing the specific molecules involved allows us to now work on creating more targeted and effective cancer drugs with fewer side effects.”

The scientists watched the drug at work in animal cells. They modified some cells to remove certain proteins and discovered the drug had different effects.

They found that arsenic helps molecules called SUMO stick onto proteins involved in leukaemia. An enzyme called RNF4 hunts down SUMO and breaks down the cancer-causing proteins.

Cancer Research UK’s director of cancer information, Dr Lesley Walker, said: “Discovering which molecules are involved in this process is an exciting step forward in understanding this complex paradox – how can a chemical that causes cancer also cure it?”

“It’s a great piece of science that will hopefully lead to the development of drugs that home in on specific cancer-causing proteins to beat the disease.”