Low-Frequency Kras Mutations are Prevalent in Lung Adenocarcinomas

Abstract

Aim: This study quantified low-frequency KRAS mutations in normal lung and lung adenocarcinomas, to understand their potential significance in the development of acquired resistance to EGFR-targeted therapies. Materials & methods: Allele-specific Competitive Blocker-PCR was used to quantify KRAS codon 12 GAT (G12D) and GTT (G12V) mutation in 19 normal lung and 21 lung adenocarcinoma samples. Results: Lung adenocarcinomas had KRAS codon 12 GAT and GTT geometric mean mutant fractions of 1.94 × 10^-4 and 1.16 × 10^-3, respectively. For 76.2% of lung adenocarcinomas, the level of KRAS mutation was greater than the upper 95% confidence interval of that in normal lung. Conclusion:KRAS mutant tumor subpopulations, not detectable by DNA sequencing, may drive resistance to EGFR blockade in lung adenocarcinoma patients.

Keywords::

• carcinogenesis
• epidermal growth factor receptor
• mutation
• mutation detection
• non-small-cell lung cancer
• oncogene
• oncogene-induced senescence
• personalized medicine
• polyclonal tumor origin
• targeted molecular therapy

Acknowledgements

The authors thank M Manjanatha and X Cao for their critical review of the manuscript. Tissue samples were provided by the Cooperative Human Tissue Network, a National Cancer Institute supported resource. Other investigators may have received samples from these same tissue specimens.

Financial & competing interests disclosure

MB Myers, KL McKim, F Meng and BL Parsons are employees of the US FDA. The opinions and information presented are those of the authors, and do not represent the views and/or policies of the US FDA, nor does the mention of trade names or commercial products constitute endorsement or recommendation for use. The authors acknowledge use of tissues procured by the National Disease Research Interchange (NDRI; with support from NIH grant 5U42 RR006042). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

MB Myers, KL McKim, F Meng and BL Parsons are employees of the US FDA. The opinions and information presented are those of the authors, and do not represent the views and/or policies of the US FDA, nor does the mention of trade names or commercial products constitute endorsement or recommendation for use. The authors acknowledge use of tissues procured by the National Disease Research Interchange (NDRI; with support from NIH grant 5U42 RR006042). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.