Novel mutations in tyrosine kinase domain of epidermal growth factor receptor in prostate cancer

Abstract

4611 Background: We recently reported that EGFR protein overexpression is significantly more common in African American (AA) prostate cancer patients compared to White patients (Shuch et al. 2004 JCO, 22:4673–4677). In the current study, we further explore EGFR dysregulation in prostate cancer patients of different ethnicities by examining mutations in the EGFR tyrosine kinase (TK) domain. In addition to AA and White prostate cancer patients, we included South Korean patients in light of recent reports that EGFR mutations are more common in Asian patients with non-small cell lung cancer. Methods: Normal and tumor DNA from radical prostatectomy cases (n = 89: Koreans n = 36, AA n = 27, Whites n = 26) were studied for mutations in the EGFR TK domain using genomic DNA sequencing. Results: We identified 4/89 (5%) novel missense mutations in exons 19, 20 and 21 of TK domain: 3 in Koreans (8%, 95%, CI = 2%– 22%) and 1 in White (4%, 95% CI = 0.1%–20%) but none in AA. These mutations, which were not described before, are expected to affect TK activity based on the change of the amino acid phosphorylation pattern and the 3-dimensional structure of TK domain. We also identified 5 distinct synonymous DNA sequence changes in exons 20 and 21 in 31/89 (35%) patients. These synonymous sequence changes were not observed in the corresponding normal DNA in 8/31 (25.8%) patients, indicating the presence of de novo somatic mutation in those patients, and are likely to affect mRNA splicing leading to altered EGFR protein transcripts. Conclusions: Several independent mechanisms of EGFR dysregulation operate in prostate cancer including EGFR protein overexpression, missense mutations, and somatic synonymous sequence changes in the TK domain. Validation on a larger sample size in addition to functional studies are needed to determine the specific association between a patient’s ethnicity, EGFR dysregulation, and response to EGFR inhibitors in prostate cancer. No significant financial relationships to disclose.