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Heterogeneous distribution of K-ras mutations in primary colon carcinomas: implications for EGFR-directed therapy

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Abstract

Purpose

K-ras mutations predict resistance against epidermal growth factor receptor (EGFR)-directed therapy of metastatic colorectal cancer (CRC). The purpose of this study was to analyze the distribution of K-ras mutations in primary tumors and corresponding sentinel lymph nodes (SLNs) from colon cancer patients.

Methods

Tumor biopsies and SLNs from 158 patients with non-metastatic colon cancer were analyzed for K-ras mutations in codons 12 and 13 by a sensitive and quantitative peptide nucleic acid clamp PCR assay.

Results

Analyses of single fresh-frozen tumor biopsies revealed K-ras mutations in 67 (42%) of the patients. Apparently low levels of K-ras mutations in 13 of the mutated primary tumors and the presence of K-ras mutations in SLNs from seven patients with a wild-type primary tumor biopsy suggested possible intratumoral heterogeneity for 20 of the patients. To confirm this hypothesis, we analyzed tissue sections from all available formalin-fixed, paraffin-embedded (FFPE) tumor blocks from these 20 patients. Ten of the patients had a mixture of tissue sections positive and tissue sections negative for K-ras mutations, two patients had K-ras mutations in all sections, and eight patients had no detectable K-ras mutations in tumor FFPE tissue blocks. Among these eight patients, five had K-ras mutations detected in SLNs. Thus, evidence supporting a heterogeneous distribution of K-ras mutations was obtained for 15 patients.

Conclusions

Heterogeneous distribution of K-ras codon 12 and 13 mutations within primary tumor, or between primary tumor and lymph node metastases, was demonstrated for 15 (20%) of 74 colon cancer patients having K-ras mutations. This may have implications for tissue sampling routines with regard to EGFR-directed therapy of CRC, both in adjuvant and metastatic settings.

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Acknowledgments

We thank Anne Elin Varhaugvik for technical assistance. The study was supported by the Western Norway Regional Health Authorities, the Norwegian Cancer Society, the Folke Hermansen Fund, and Stavanger University Hospital.

Conflict of interest

The authors have no conflict of interest.

Author information

Author notes

  1. Reino Heikkilä

    Present address: , Roche Norge AS, Oslo, Norway

Authors and Affiliations

  1. Laboratory for Molecular Biology, Stavanger University Hospital, PO Box 8100, 4068, Stavanger, Norway

    Satu Oltedal, Kjersti Tjensvoll, Rune Smaaland & Oddmund Nordgård

  2. Department of Pathology, Stavanger University Hospital, Stavanger, Norway

    Ole Gunnar Aasprong

  3. Department of Hematology and Oncology, Stavanger University Hospital, Stavanger, Norway

    Jannicke H. Møller, Bjørnar Gilje, Elke M. Birkemeyer, Reino Heikkilä, Rune Smaaland & Oddmund Nordgård

  4. Department of Surgery, Stavanger University Hospital, Stavanger, Norway

    Hartwig Kørner

  5. Department of Surgical Sciences, University of Bergen, Bergen, Norway

    Hartwig Kørner

  6. Institute of Medicine, University of Bergen, Bergen, Norway

    Rune Smaaland

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  1. Satu Oltedal
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Correspondence to Oddmund Nordgård.

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Oltedal, S., Aasprong, O.G., Møller, J.H. et al. Heterogeneous distribution of K-ras mutations in primary colon carcinomas: implications for EGFR-directed therapy. Int J Colorectal Dis 26, 1271–1277 (2011). https://doi.org/10.1007/s00384-011-1233-5

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  • DOI: https://doi.org/10.1007/s00384-011-1233-5

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