Met Mutation is a Potential Therapeutic Target for Advanced Endometrial Cancer 

Abstract BackgroundAn optimal therapeutic regimen for endometrial cancer with extra-uterine metastasis is unavailable. This study aimed to improve our understanding about the genomic landscape of advanced endometrial cancer and identify potential therapeutic targets.MethodsThe clinical and genomic profiles of 81 patients with stage III or IV endometrial cancer were integrated. The genomic landscape was compared with that of The Cancer Genome Atlas (TCGA) cohort. To identify genomic aberrations associated with clinical outcome, Cox proportional hazard regression was used. The impacts of the genomic aberrations were validated in vitro and in vivo. ResultsA discrepancy in major genetic aberrations that contributed to the genomic functions was observed between the present study and TCGA cohorts. The mutation status of MET, U2AF1, BCL9, PPP2R1A, IDH2, CBL, BTK, and CHEK2 were positively correlated with poor clinical outcomes. MET mutations occurred in 30% of the patients who presented with poor overall survival (hazard ratio, 2.606; 95% confidence interval, 1.167~5.819; adjusted p-value, 0.067). Concurrent MET and KRAS mutations presented with the worst outcomes. MET mutations in HGF-binding (58.1%) or kinase (16.2%) domains resulted in differential HGF-induced c-MET phosphorylation. Different types of MET mutations differentially affected tumor growth and displayed different sensitivities to cisplatin and tyrosine kinase inhibitors. MET N375S mutation is a germline variant with a high incidence in Eastern Asia and causes chemoresistance to cisplatin.ConclusionsThis study highlights the ethnic differences in the biology of the disease, which can influence the treatment recommendations and the genome-guided clinical trials of advanced endometrial cancer.