Analysis of the dinucleotide repeat polymorphism in the epidermal growth factor receptor (EGFR) in tumor and normal tissue of head and neck cancer (HNC) patients

Abstract

5518 Background: EGFR plays a major role in cell proliferation. EGFR overexpression is strongly associated with poor prognosis in HNC patients. First intron of EGFR gene contains a highly polymorphic microsatellite sequence (9 to 23 CA-repeats) and in vitro transcription declines with increasing number of repeats. We analyzed EGFR gene polymorphism and EGFR expression in tumor (T) and normal mucosa (N) of HNC patients. Methods: T biopsies (initial diagnosis) were taken in 113 patients (mean age 60, 101 men, 12 women; 13 stage II, 21 stage III, 79 stage IV; 53 cancer-related deaths) along with N biopsies for 100 patients. EGFR levels were measured by ligand-binding assay. The microsatellite marker was analyzed by semi-automated fluorescent genotyping. Prognostic values of EGFR genotype and expression on specific survival were analyzed by multivariate Cox regression including performance status and node involvement. Results: Number of CA repeats varied from 13 to 22. Allelic distribution in tumor was trimodal : 49 % 16 CA, 17.5 % 20 CA, 15.5 % 18 CA. A similar pattern was observed in N samples. Heterozygosity was 60 % and 65% in T and N, respectively. In 33% of patients genotype was discordant between T and N, strongly suggesting high EGFR microsatellite instability. There was no relationship between EGFR genotype and EGFR expression (by considering either the shorter allele, the longer, homozygous samples, samples having a common allele, or classifying genotypes as short/long/intermediary defined as 2 alleles<17 vs 2 alleles[tmsnew]63[/tmsnew]17 vs others). Cox analysis confirmed the prognostic significance of T EGFR expression (p = 0.030). T EGFR genotype did not influence survival. A poorer survival was observed in patients with short repeats in normal mucosa (short/long/intermediary, p = 0.040). Patients with EGFR microsatellite instability exhibited significantly shorter survival (p = 0.013). Furthermore, EGFR microsatellite instability (p = 0.003) and T EGFR expression (p = 0.009) were independent significant survival predictors. Conclusion: These promising new findings shed a new light on EGFR implication in HNC. No significant financial relationships to disclose.