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

Liu C, Karam R, Zhou Y, Su F, Ji Y, Li G, Xu G, Lu L, Wang C, Song M, Zhu J, Wang Y, Zhao Y, Foo WC, Zuo M, Valasek MA, Javle M, Wilkinson MF, Lu Y - Nat. Med. (2014)

Bottom Line: Pancreatic adenosquamous carcinoma (ASC) is an enigmatic and aggressive tumor that has a worse prognosis and higher metastatic potential than its adenocarcinoma counterpart.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Clinical and Translational Cancer Research Center, The Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. [2] Tongji University School of Life Science and Technology, Shanghai, China. [3].

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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Somatic UPF1 mutations in ASC tumors. (a) Chromatograms of UPF1 DNA sequences from tumor (TU) and normal adjacent pancreatic tissue (NP). A total of 36 single-base substitutions in genomic UPF1 DNA were found in the tumors; each patient had between one to five point mutations. All NP samples had wild-type UPF1 sequences, indicating mutations were somatic in origin. (b) Top: schematic of UPF1 protein domains. Bottom: the type and location of mutations found in the two regions of UPF1 that harbored mutations. ESEs and ISEs are exonic and intronic splicing enhancers, respectively (sequences are provided on Supplementary Figure 2).
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Figure 1: Somatic UPF1 mutations in ASC tumors. (a) Chromatograms of UPF1 DNA sequences from tumor (TU) and normal adjacent pancreatic tissue (NP). A total of 36 single-base substitutions in genomic UPF1 DNA were found in the tumors; each patient had between one to five point mutations. All NP samples had wild-type UPF1 sequences, indicating mutations were somatic in origin. (b) Top: schematic of UPF1 protein domains. Bottom: the type and location of mutations found in the two regions of UPF1 that harbored mutations. ESEs and ISEs are exonic and intronic splicing enhancers, respectively (sequences are provided on Supplementary Figure 2).

Mentions: The alternative splicing event creating this p53 isoform generates an in-frame premature termination codon (PTC) in intron 6 (Supplementary Fig. 1b). Because NMD degrades mRNAs with PTCs6,7, the selective accumulation of this “alt-PTC-IVS6-p53” mRNA in the tumor tissue but not the adjacent normal tissue, raised the possibility that the tumor tissue had deficient NMD. To test this, we screened ASC tumor samples for mutations in core NMD genes. We found genomic mutations in the UPF1 gene in ASC tumors from 18 of 23 patients (see TU in Fig. 1a), whereas the 3 other NMD genes we tested—UPF2, UPF3A, and UPF3B—did not have detectable mutations (Supplementary Table 1). The UPF1 mutations were somatic in origin, since they were not present in matched normal pancreatic tissues from these 18 patients (see NP in Fig. 1a). UPF1 mutations were also not present in 50 non-ASC pancreatic and SCC lung tumors that we tested (Supplementary Table 2). Together, these results suggest that UPF1 mutations are a unique signature of ASC pancreatic tumors.


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

Liu C, Karam R, Zhou Y, Su F, Ji Y, Li G, Xu G, Lu L, Wang C, Song M, Zhu J, Wang Y, Zhao Y, Foo WC, Zuo M, Valasek MA, Javle M, Wilkinson MF, Lu Y - Nat. Med. (2014)

Somatic UPF1 mutations in ASC tumors. (a) Chromatograms of UPF1 DNA sequences from tumor (TU) and normal adjacent pancreatic tissue (NP). A total of 36 single-base substitutions in genomic UPF1 DNA were found in the tumors; each patient had between one to five point mutations. All NP samples had wild-type UPF1 sequences, indicating mutations were somatic in origin. (b) Top: schematic of UPF1 protein domains. Bottom: the type and location of mutations found in the two regions of UPF1 that harbored mutations. ESEs and ISEs are exonic and intronic splicing enhancers, respectively (sequences are provided on Supplementary Figure 2).
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Related In: Results  -  Collection

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Figure 1: Somatic UPF1 mutations in ASC tumors. (a) Chromatograms of UPF1 DNA sequences from tumor (TU) and normal adjacent pancreatic tissue (NP). A total of 36 single-base substitutions in genomic UPF1 DNA were found in the tumors; each patient had between one to five point mutations. All NP samples had wild-type UPF1 sequences, indicating mutations were somatic in origin. (b) Top: schematic of UPF1 protein domains. Bottom: the type and location of mutations found in the two regions of UPF1 that harbored mutations. ESEs and ISEs are exonic and intronic splicing enhancers, respectively (sequences are provided on Supplementary Figure 2).
Mentions: The alternative splicing event creating this p53 isoform generates an in-frame premature termination codon (PTC) in intron 6 (Supplementary Fig. 1b). Because NMD degrades mRNAs with PTCs6,7, the selective accumulation of this “alt-PTC-IVS6-p53” mRNA in the tumor tissue but not the adjacent normal tissue, raised the possibility that the tumor tissue had deficient NMD. To test this, we screened ASC tumor samples for mutations in core NMD genes. We found genomic mutations in the UPF1 gene in ASC tumors from 18 of 23 patients (see TU in Fig. 1a), whereas the 3 other NMD genes we tested—UPF2, UPF3A, and UPF3B—did not have detectable mutations (Supplementary Table 1). The UPF1 mutations were somatic in origin, since they were not present in matched normal pancreatic tissues from these 18 patients (see NP in Fig. 1a). UPF1 mutations were also not present in 50 non-ASC pancreatic and SCC lung tumors that we tested (Supplementary Table 2). Together, these results suggest that UPF1 mutations are a unique signature of ASC pancreatic tumors.

Bottom Line: Pancreatic adenosquamous carcinoma (ASC) is an enigmatic and aggressive tumor that has a worse prognosis and higher metastatic potential than its adenocarcinoma counterpart.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Clinical and Translational Cancer Research Center, The Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. [2] Tongji University School of Life Science and Technology, Shanghai, China. [3].

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.

Show MeSH
Related in: MedlinePlus