Somatic mutations of EGFR signal transducers and expression of tumor suppressor PTEN in biliary tract carcinoma

Abstract

4582 Background: Biliary tract carcinomas express EGFR and are potential candidates to EGFR target therapies. We recently described somatic mutations of EGFR that can enhance MAPK or Akt activation (Clin Cancer Res, 2006). Some of them are identical to those previously reported to confer sensitivity to some tyrosine kinase inhibitors (TKIs) like erlotinib or gefitinib in lung cancer. Here we report a molecular analysis of EGFR transducers potentially involved in TKI response. Methods: In 49 samples of biliary tract carcinoma we performed mutational analysis of exons from 18 to 21 of EGFR, exons 9 and 20 of phosphatidylinositol 3’-kinase (PI3K), exon 2 of K-Ras, exon 15 of B-Raf and exons from 5 to 8 of PTEN. Nuclear PTEN expression was analyzed by immunohistochemistry and the expression in cancer cells was compared to that of normal cholangiocites. Results: Mutations of EGFR have been detected in 7 out of 49 samples (14.3%). One of them was a new stop-codon mutation. Five hotspot mutations of PI3K (codon 545, 546, 1048 and 1059) were found in 4 cases (8.2%); 3 cases (6.1%) had single mutations in K-Ras and 4 (8.2%) had the V599E mutation in B-Raf. In some samples, mutations of multiple trasducers were present simultaneously. PI3K mutations were significantly more frequent in EGFR mutated samples compared to wild type (28% vs. 4.7% respectively, p<0.05). A single F271L mutation of PTEN was observed (2%). We did not find loss of nuclear PTEN in biliary tract carcinoma cells; rather, a stronger labelling intensity (score 2+ or 3+) was present in biliary tract carcinoma compared to normal cholangiocites (score 1+). Moreover, the median percentage of PTEN labeled nuclei in tumor cells was 31.8%, but in samples with activating EGFR mutation was 60%, suggesting that a compensatory change in the level of the phosphatase might counteract the EGFR activition. Conclusions: These results corroborate our previous finding of EGFR pathway activation in EGFR mutated biliary tract carcinoma and suggest that an accurate analysis of the entire series of EGFR transducers may be done before planning treatments with TKIs. No significant financial relationships to disclose.