Mutational profiling of protein kinases in prostate carcinoma.

4636 Background: Protein kinases are important signal transduction mediators that play a critical role in malignant transformation. However, their involvement in prostate carcinogenesis has not been fully elucidated.,In this pilot study, we sequenced the coding and exon-flanking intronic regions of selected protein kinases in 15 human prostate carcinoma specimens and 2 prostate cancer cell lines using standard techniques (Agencourt Biosciences). The 15 protein kinases genes included: tyrosine kinases (EGFR, EPHA3, EPHB2, ERBB2, FES, FGFR2, KDR, KIT, MET, NTRK1, NTRK2, NTRK3), tyrosine kinase-like (BRAF), serine/threonine kinase (AKT2), and the lipid kinase (PIK3CA). We also sequenced PTEN, p53 and AR because of their known association with prostate cancer and interactions with protein kinases.,We identified 452 different sites of single nucleotide sequence alterations and 50 insertion/deletion changes in multiple genes in the 17 specimens. The majority were intronic or involved untranslated regions (364 single nucleotide and all indels), and therefore were not further evaluated. Of the remaining 88 coding region alterations, 59 were synonymous and 10 were previously identified single nucleotide polymorphisms leaving 19 non-synonymous coding region changes (12 in 12 patient tumors and 9 in cell lines). Sequencing of corresponding non-neoplastic tissue revealed that 4 genes with sequence alterations were also altered in the germ-line and likely represent polymorphisms (EPHA3, KDR, NTRK1 and NTRK3). Six tumor specific mutation sites have been confirmed (one mutation is yet to be studied). Three represent unreported sites of mutation in prostate cancer involving MET (1 site) and EPHB2 (2 sites) and the others involved known sites within AR (1 site) and TP53 (2 sites).,Our study successfully identified specific mutations of tyrosine kinases occurring in prostate cancer. Evaluation of a larger sample representing natural and treated history of prostate cancer to determine frequency and clinical associations, as well as functional studies to determine the biological significance of these mutations, is needed. No significant financial relationships to disclose.