Abstract
Purpose
Mucosal melanoma is a relatively rare subtype of melanoma for which no clearly established therapeutic strategy exists. The genes of the mTOR signalling pathway have drawn great attention as key targets for cancer treatment, including melanoma. In this study, we aimed to investigate the mutation status of the upstream mTOR regulator TSC1 and evaluated its correlation with the clinicopathological features of mucosal melanoma.
Methods
We collected 91 mucosal melanoma samples for detecting TSC1 mutations. All the coding exons of TSC1 were amplified by PCR and subjected to Sanger sequencing. Expression level of TSC1 encoding protein (hamartin) was detected by immunohistochemistry. The activation of mTOR pathway was determined by evaluating the phosphorylation status of S6RP and 4E-BP1.
Results
The overall mutation frequency of TSC1 was found to be 17.6% (16/91 patients). TSC1 mutations were more inclined to occur in advanced mucosal melanoma (stages III and IV). In the 16 patients with TSC1 mutations, 14 different mutations were detected, affecting 11 different exons. TSC1 mutations were correlated with upregulation of S6RP phosphorylation but were unrelated to 4E-BP1 phosphorylation or hamartin expression. Mucosal melanoma patients with TSC1 mutations had a worse outcome than patients without TSC1 mutations (24.0 versus 34.0 months, P = 0.007).
Conclusions
Our findings suggest that TSC1 mutations are frequent in mucosal melanoma. TSC1 mutations can activate the mTOR pathway through phospho-S6RP and might be a poor prognostic predictor of mucosal melanoma. Our data implicate the potential significance of TSC1 mutations for effective and specific drug therapy for mucosal melanoma.
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Acknowledgements
The authors thank the staff in the Department of Pathology of our hospitalfor help in collection and pathologic analysis of tissue samples.
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This study was funded by grants from the National Natural Science Foundation of China (51402264, 81672696), Beijing Talents Fund (2016000021223ZK18), Beijing Municipal Natural Science Foundation (7152033), Baiqianwan Talents Project, Beijing Municipal Administration of Hospitals Clinical medicine Development of special funding support (ZYLX201603), and Beijing Municipal Science & Technology Commission (Z151100003915074).
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The authors declare that they have no conflict of interest.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the Medical Ethics Committee of the Beijing Cancer Hospital & Institute and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.
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Informed consent was obtained from all individual participants included in the study.
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Ma, M., Dai, J., Xu, T. et al. Analysis of TSC1 mutation spectrum in mucosal melanoma. J Cancer Res Clin Oncol 144, 257–267 (2018). https://doi.org/10.1007/s00432-017-2550-z
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DOI: https://doi.org/10.1007/s00432-017-2550-z