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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.

SUBMITTER: Liu C

PROVIDER: S-EPMC4048332 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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

Liu Chen C Karam Rachid R Zhou YingQi Y Su Fang F Ji Yuan Y Li Gang G Xu GuoTong G Lu LiXia L Wang ChongRen C Song MeiYi M Zhu JingPing J Wang YiRan Y Zhao YiFan Y Foo Wai Chin WC Zuo MingXin M Valasek Mark A MA Javle Milind M Wilkinson Miles F MF Lu YanJun Y

Nature medicine 20140525 6

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, ...[more]

PMID: 24859531

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The origins and consequences of <i>UPF1</i> variants in pancreatic adenosquamous carcinoma.

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The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma

Project description:Pancreatic adenosquamous carcinoma (PASC) is an aggressive cancer whose mutational origins are poorly understood. An early study reported high-frequency somatic mutations affecting UPF1, a core nonsense-mediated mRNA decay (NMD) factor, in PASC, but subsequent studies did not observe these lesions. The corresponding controversy about whether UPF1 mutations are important contributors to PASC has been exacerbated by a paucity of functional studies. Here, we modeled two UPF1 mutations to find no significant effects on pancreatic cancer growth, acquisition of adenosquamous features, UPF1 splicing, UPF1 protein levels, or NMD efficiency. We subsequently discovered that ~40% of UPF1 mutations reportedly present in PASCs are identical to standing genetic variants in the human population, suggesting that they may be non-pathogenic inherited variants rather than pathogenic mutations. Our data suggest that UPF1 is not a common functional driver of PASC and motivate further attempts to identify unique genetic features defining these malignancies.

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Project description: Not available

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