KRAS and NRAS mutations render resistance to EGFR therapeutic antibodies. Some data indicate that erroneous administration of cetuximab or panitumumab to patients with RAS-mutated colorectal cancer (CRC) may even accelerate tumour growth.
1501 CRC patients were included in the analysis. High-resolution melting (HRM) was performed for the initial screening of KRAS and NRAS mutations in exons 2, 3 and 4. Common RAS mutations were detected by allele-specific PCR, then the remaining samples were analysed by pyrosequencing.
RAS mutations were identified in 756 (50.4%) CRCs. KRAS and NRAS alterations were generally mutually exclusive, with the exception of 2 CRCs carrying lesions in both oncogenes. Distribution or RAS mutations did not show correlation with age or gender. Significant number of the revealed mutations are not included in the spectrum of substitutions covered by commercial kits. For 681 identified KRAS mutations, the following coverage is expected according to manufacturer’s brochures: Therascreen (Qiagen): 592 (86.9%); cobas® (Roche, US version): 615 (90.3%); AmoyDx: 665 (97.7%); KRAS StripAssay® (ViennaLab): 600 (88.1%); KRAS XL StripAssay® (ViennaLab): 671 (98.5%). For 77 detected NRAS mutations, these estimates would be 73 (94.8%) for AmoyDx and 75 (97.4%) for NRAS XL StripAssay® (ViennaLab).
Clinically significant share of KRAS and NRAS mutations is likely to be missed by conventional mutation-specific diagnostic kits. This limitation has to be considered while defining diagnostic standards for CRC therapy.
Clinical trial identification
Legal entity responsible for the study
Russian Society of Clinical Oncology.
All authors have declared no conflicts of interest.