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The UPF1 RNA surveillance gene is commonly mutated in pancreatic adenosquamous carcinoma

Abstract

Pancreatic adenosquamous carcinoma (ASC) is an enigmatic and aggressive tumor that has a worse prognosis and higher metastatic potential than its adenocarcinoma counterpart. Here we report that ASC tumors frequently harbor somatically acquired mutations in the UPF1 gene, which encodes the core component of the nonsense-mediated RNA decay (NMD) pathway. These tumor-specific mutations alter UPF1 RNA splicing and perturb NMD, leading to upregulated levels of NMD substrate mRNAs. UPF1 mutations are, to our knowledge, the first known unique molecular signatures of pancreatic ASC.

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Figure 1: Somatic UPF1 mutations in pancreatic ASC tumors.
Figure 2: ASC-specific UPF1 mutations trigger alternative UPF1 RNA splicing.

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Acknowledgements

This work was supported by the National Key Basic Research Program of China grants 2013CB967500 and 2011DFB30010 (to G.X.) and 2011CB965102 (to L.L.), the National Natural Science Foundation of China grant 81071740 (to Y.J.) and a US National Institutes of Health grant (to M.F.W.). Vector pTBNde(mini) was provided by F.E. Baralle (International Centre for Genetic Engineering and Biotechnology, Italy).

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Authors

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C.L., R.K., Y. Zhao, F.S., C.W., M.S., Y.W., G.X., L.L. and J.Z. performed the experiments. Y. Zhou, Y.J., G.L., W.C.F., M.Z., M.A.V. and M.J. provided clinical samples and expertise on pancreatic cancer. R.K. and C.L. prepared the figures and tables and wrote the manuscript. Y.L. and M.F.W. equally contributed to this study by designing and supervising all experiments and assisting in writing the manuscript.

Corresponding authors

Correspondence to Miles F Wilkinson or YanJun Lu.

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The authors declare no competing financial interests.

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Liu, C., Karam, R., Zhou, Y. et al. The UPF1 RNA surveillance gene is commonly mutated in pancreatic adenosquamous carcinoma. Nat Med 20, 596–598 (2014). https://doi.org/10.1038/nm.3548

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