Acquired/intratumoral mutation of KRAS during metastatic progression of colorectal carcinogenesis

Mutations at codons 12 and 13 of the KRAS gene have been identified as level I predictive biomarkers against the treatment of advanced colorectal cancer with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies. It is thought that the genetic analysis of KRAS mutations associated with metastatic colorectal cancer can be routinely conducted using DNA obtained on one occasion from one organ, from the primary or a metastatic site, whichever is preferentially available. However, the issue of tumor heterogeneity resulting from acquired/intratumoral mutations remains. Recently, the possibility of acquired/intratumoral mutations in the KRAS gene has been reported by two research groups and has ranged from 7.4 to 15.4%. Specimens were collected from advanced colorectal cancer patients with resected primary, and at least one metastatic, site. Direct sequence analysis was performed for KRAS, BRAF and PIK3CA, and immunohistochemistry for glutathione S-transferase II (GSTP) and EGFR. In the current study, we identified an acquired mutation rate of approximately 11.1% in the KRAS gene (1/9). This figure is not negligible. Our observation indicates, particularly in the case of metastatic recurrence after a long interval, that there may be considerable tumor heterogeneity resulting from acquired or intratumoral mutations of the KRAS gene.