Mutational analysis of the tyrosine kinome in serous and clear cell endometrial cancer uncovers rare somatic mutations in TNK2 and DDR1Reportar como inadecuado




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BMC Cancer

, 14:884

Genetics, genomics and epigenetics

Abstract

BackgroundEndometrial cancer EC is the 8 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.

MethodsIn 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.

ResultsOverall, 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 frameshift mutation was recurrent in EC, and the DDR1 missense mutation was recurrent across tumor types.

ConclusionsThis 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.

KeywordsEndometrial Cancer Mutation TNK2 ACK1 DDR1 Copy number Tyrosine kinase Tyrosine kinome AbbreviationsB2MBeta-2-microglobulin

DDR1Discoidin domain receptor tyrosine kinase 1

ECEndometrial carcinoma

EECsEndometrioid endometrial carcinomas

HandEHematoxylin and eosin

MSIMicrosatellite instability

POLEPolymerase DNA directed epsilon catalytic subunit

TCGAThe cancer genome atlas

TNK2Tyrosine kinase non-receptor 2

UBAUbiquitin associated.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-14-884 contains supplementary material, which is available to authorized users.

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Autor: Meghan L Rudd - Hassan Mohamed - Jessica C Price - Andrea J O’Hara - Matthieu Le Gallo - Mary Ellen Urick - NISC Compa

Fuente: https://link.springer.com/







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