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Research
Met Mutation is a Potential Therapeutic Target for Advanced Endometrial Cancer
Meng-Ru Shen
Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Taiwan;
Corresponding Author
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
An 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.
Methods
The 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.
Results
A 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.
Conclusions
This 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.
Keywords
endometrial cancer, MET mutation, germline variant, targeted therapy, chemoresistance
Figure 1
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Figure 4
This is a list of supplementary files associated with this preprint. Click to download.
- SupplementaryFigureS720200710.jpg
Supplementary Figure S7. DNA polymerase epsilon (POLE) mutations in advanced endometrial cancer.
- SupplementaryFigureS620200710.jpg
Supplemental Figure S6. Comparison between TCGA and NCKUH cohort.
- SupplementaryFigureS520200710.jpg
Supplementary Figure S5. SCID mice were subcutaneously inoculated with endometrial cancer RL95-2 cells carrying either wild type or mutant MET (N375S, G1085R, or G1087E).
- SupplementaryFigureS4.jpg
Supplementary Figure S4. Effect of MET mutations on the cellular function of endometrial cancer KLE cell line.
- SupplementaryFigureS3.jpg
Supplementary Figure S3. The potential effects of MET mutations on protein structure.
- SupplementaryFigureS2.jpg
Supplementary Figure S2. MET mutational patterns and overall survival.
- SupplementaryFigureS1.jpg
Additional file 2: Supplementary Figure S1. Impact of MET mutation and concurrent genetic mutations on clinical outcome of advanced endometrial cancer.
- SupplementaryTableS120200626.docx
Additional file 1: Supplementary Table S1. Patient characteristics.
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This is a preprint. It has not completed peer review.
Research
Met Mutation is a Potential Therapeutic Target for Advanced Endometrial Cancer
Meng-Ru Shen
Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Taiwan;
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 28 Sep, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Biomedical Engineering
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
An 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.
Methods
The 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.
Results
A 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.
Conclusions
This 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.
Figure 1
Figure 2
Figure 3
Figure 4