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Background  Endometrial cancer (EC) is the 8 th  leading cause of cancer death amongst American women. Most ECs are endometrioid, serous, or clear cell carcinomas, or an admixture of histologies. Serous and clear ECs are clinically aggressive tumors for which alternative therapeutic approaches are needed. The purpose of this study was to search for somatic mutations in the tyrosine kinome of serous and clear cell ECs, because mutated kinases can point to potential therapeutic targets.    Methods  In a mutation discovery screen, we PCR amplified and Sanger sequenced the exons encoding the catalytic domains of 86 tyrosine kinases from 24 serous, 11 clear cell, and 5 mixed histology ECs. For somatically mutated genes, we next sequenced the remaining coding exons from the 40 discovery screen tumors and sequenced all coding exons from another 72 ECs (10 clear cell, 21 serous, 41 endometrioid). We assessed the copy number of mutated kinases in this cohort of 112 tumors using quantitative real time PCR, and we used immunoblotting to measure expression of these kinases in endometrial cancer cell lines.    Results  Overall, we identified somatic mutations in  TNK2  (tyrosine kinase non-receptor, 2) and  DDR1  (discoidin domain receptor tyrosine kinase 1) in 5.3% (6 of 112) and 2.7% (3 of 112) of ECs. Copy number gains of  TNK2  and  DDR1  were identified in another 4.5% and 0.9% of 112 cases respectively. Immunoblotting confirmed TNK2 and DDR1 expression in endometrial cancer cell lines. Three of five missense mutations in  TNK2  and one of two missense mutations in  DDR1  are predicted to impact protein function by two or more  in silico  algorithms. The TNK2 P761Rfs*72  frameshift mutation was recurrent in EC, and the DDR1 R570Q  missense mutation was recurrent across tumor types.    Conclusions  This is the first study to systematically search for mutations in the tyrosine kinome in clear cell endometrial tumors. Our findings indicate that high-frequency somatic mutations in the catalytic domains of the tyrosine kinome are rare in clear cell ECs. We uncovered ten new mutations in  TNK2  and  DDR1  within serous and endometrioid ECs, thus providing novel insights into the mutation spectrum of each gene in EC.    Electronic supplementary material  The online version of this article (doi:10.1186/1471-2407-14-884) contains supplementary material, which is available to authorized users.

Mutational analysis of the tyrosine kinome in serous and clear cell endometrial cancer uncovers rare somatic mutations in TNK2 and DDR1