Oncogenic levels of mitogen-activated protein kinase (MAPK) signaling of the dinucleotide KRAS2 mutations G12F and GG12-13VC.

We previously reported the occurrence of novel dinucleotide mutations of the K-RAS gene (KRAS2) in 2% of pancreatic tumors sampled, but it remained unknown whether these were functional mutations that convert the proto-oncogene to an oncogene, or unselected mutations that might inactivate protein function. In the current study, the functionality of these rare mutations was quantitated via a mitogen-activated protein kinase (MAPK) pathway-specific transactivational reporter system. Pathway activation by dinucleotide mutant proteins was comparable to that of the common G12V mutant K-Ras protein. Current allele-specific technologies often employed to detect K-RAS mutations in clinical tumor samples produce false results when dinucleotide mutations are present. Therefore, it is advisable to consider dinucleotide KRAS2 mutants in the strategic design of mutational screens used to assay clinical tumor samples. Hum Mutat 18:357, 2001.