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

BMC Cancer

Daphne W Bell⁵  Maria J Merino⁶  James C Mullikin¹  Tyra G Wolfsberg¹  Dennis C Sgroi⁴  Andrew K Godwin³  Nancy F Hansen¹  Suiyuan Zhang¹  Pedro Cruz¹  NISC Comparative Sequencing Program²  Mary Ellen Urick⁵  Matthieu Le Gallo⁵  Andrea J O’Hara⁵  Jessica C Price⁵  Hassan Mohamed⁵  Meghan L Rudd⁵ 

[1]Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda MD 20892, USA

[2]NIH Intramural Sequencing Center, National Institutes of Health, Bethesda MD 20892, USA

[3]Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas KS 66160, USA

[4]Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, 149 13th Street, Charlestown MA 02129, USA

[5]Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda MD 20892, USA

[6]Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, USA

关键词: Tyrosine kinome;    Tyrosine kinase;    Copy number;    DDR1;    ACK1;    TNK2;    Mutation;    Cancer;    Endometrial;   

Others  :  1117989
DOI  :  10.1186/1471-2407-14-884

 received in 2014-01-29, accepted in 2014-11-13,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Rudd et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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