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Background: In advanced colorectal cancer, K-Ras somatic mutations predict resistance to mAbs targeting epidermal growth factor receptor (EGFR). Relationships between K-Ras mutations and EGFR status have not been examined so far. We analyzed relationships between K-Ras mutations and EGFR tumoral status based on EGFR germinal polymorphisms, gene copy number and expression., Methods: Eighty colorectal tumors (stage 0-IV) and 39 normal mucosas were analyzed. K-Ras mutations at codons 12 and 13 were detected by a sensitive enrichment double PCR-restriction fragment length polymorphism (RFLP) assay. EGFR gene polymorphisms at positions -216G>T, -191C>A and 497Arg>Lys were analyzed (PCR-RFLP), along with CA repeat polymorphism in intron 1 (fluorescent genotyping) and EGFR gene copy number (PCR amplification). EGFR expression was quantified by Scatchard binding assay., Results: The number of EGFR high-affinity sites, dissociation constant (Kd), gene copy number, intron 1, -216G>T, -191C>A or 497Lys>Arg genotypes was not different between K-Ras-mutated or K-Ras-non-mutated tumors. No relationship was observed between any of the analyzed EGFR genotypes and EGFR expression. EGFR expression was not related to gene copy number. EGFR gene copy number in tumor and normal tissue was not correlated. The mean value of the tumor/normal mucosa gene copy number ratio was 1.16., Conclusions: Present data clearly show that EGFR status is independent of K-Ras mutations in colorectal tumors.

Background: Advances in the understanding of tumor biology have led to the development of targeted therapies allowing progress in colorectal cancer treatment. One of the most promising targets is the epidermal growth factor receptor (EGFR)., Method: The presence and distribution of high- and low-affinity EGFR was investigated retrospectively in a group of 82 colorectal cancer samples (43 normal colon-colon cancer paired samples) using a specific ligand binding assay (Scatchard Analysis)., Findings: A large majority of tumor samples exhibited one class of high-affinity binding sites (78%). Eighteen cases (22%) exhibited both high- and low-affinity binding sites. A wide interpatient variability was observed for the site number, with physiologically-relevant high-affinity sites ranging from 7 to 310 fmol/mg protein in tumors and from 6 to 313 fmol/mg protein in normal mucosa. A significant positive correlation was demonstrated between tumor and normal mucosa for the high-affinity Kd values and for the number of high-affinity sites, suggesting a common regulation for both tumor and normal tissue., Interpretation: These observations (i) could explain recently-reported clinically-active EGFR targeting in colorectal tumors apparently negative for EGFR, and (ii) may offer a plausible explanation for the link observed between toxicity in normal tissue (cutaneous rash) and clinical outcome of patients treated with anti-EGFR drugs. Present data extends our understanding of EGFR identity in colorectal cancer which could be useful in reconsidering the predictive tools for the identification of tumors putatively responsive to EGFR targeted therapy.