Heterogeneity of KRAS status may explain the subset of discordant KRAS status between primary and metastatic colorectal cancer

Dis Colon Rectum. 2011 Sep;54(9):1170-8. doi: 10.1097/DCR.0b013e31821d37a3.


Background: KRAS status is a useful predictive marker for anti-epidermal growth factor receptor antibody therapy.

Objective: This study aimed to examine the concordance rate of KRAS mutation status between corresponding primary and metastatic colorectal cancer lesions, and also among multiple metastatic tumors. Furthermore, we examined the heterogeneity of KRAS mutations with respect to discordant KRAS status between primary and metastatic tumors.

Design and settings: This study was retrospective in design.

Patients: Forty-three patients with primary tumors and 113 metastatic tumors were studied.

Main outcome measures: The KRAS mutational status was determined by the peptide nucleic acid clamp real-time polymerase chain reaction TaqMan assay. We also performed sequencing analysis to validate the KRAS mutational status. When KRAS status differed between primary and metastatic tumors, we examined the heterogeneity of KRAS status within individual primary tumors by microdissecting multiple samples in each patient.

Results: The frequency of KRAS mutations in primary tumors was 34.9%. A high concordance rate of KRAS (88.4-91.7%) mutations was observed between primary and metastatic tumors. All 5 cases (11.6%) with discordant KRAS status had heterogeneous KRAS status in primary tumors. However, in 10 concordant cases all microdissected areas showed an identical KRAS mutational status within each patient. The KRAS mutational statuses in all multiple liver and/or lung metastatic tumors were the same as those of the primary tumor.

Limitations: We could not validate KRAS status in microdissected samples by the direct sequence method that was used in the present study, because the quantity of DNA was not sufficient to perform direct sequencing.

Conclusion: KRAS status in a primary site may be used for selecting patients who would benefit from anti-epidermal growth factor receptor therapy. However, KRAS status can be heterogeneous within a primary tumor, and thus different parts of such tumors should be examined for KRAS status to correctly predict the KRAS status in metastatic lesions.

MeSH terms

  • Biomarkers, Tumor
  • Chi-Square Distribution
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • ErbB Receptors / antagonists & inhibitors
  • Female
  • Humans
  • Male
  • Mutation
  • Neoplasm Metastasis
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins p21(ras)
  • Retrospective Studies
  • Reverse Transcriptase Polymerase Chain Reaction
  • ras Proteins / genetics*


  • Biomarkers, Tumor
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • ErbB Receptors
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins