Abstract
Mutations in the RNA surveillance gene UPF1 occur in 78% of pancreatic adenosquamous carcinomas (ASC).
Major finding: Mutations in the RNA surveillance gene UPF1 occur in 78% of pancreatic adenosquamous carcinomas (ASC).
Concept: The mutations alter UPF1 splicing and eliminate domains required for nonsense-mediated RNA decay (NMD).
Impact: UPF1 mutations and defective NMD may distinguish pancreatic ASC from other pancreatic cancers.
Pancreatic adenosquamous carcinoma (ASC) is a rare pancreatic cancer subtype that is more aggressive and lethal than pancreatic adenocarcinoma, yet no distinguishing molecular features have been identified. Upon noting an alternative splicing event that generated a TP53 transcript with an in-frame premature termination codon in a pancreatic ASC sample, Liu and colleagues hypothesized that nonsense-mediated RNA decay (NMD) might be impaired given that transcripts with premature termination codons are normally eliminated by this RNA surveillance mechanism. A screen for mutations in essential NMD genes revealed somatic mutations in up-frameshift 1 (UPF1) in 18 of 23 (78%) ASC samples. UPF1 mutations appeared to be specific to pancreatic ASC, as no other NMD genes were mutated in these tumors and UPF1 mutations were not found in non-ASC pancreatic cancer or lung squamous cell carcinoma samples. Two distinct clusters of UPF1 mutations were distributed in both exons and introns and affected predicted intronic and exonic splicing enhancers, raising the possibility that the mutations disrupted UPF1 mRNA splicing. Indeed, inclusion of the UPF1 mutations in minigene constructs significantly increased alternative splicing of UPF1, and tumor-specific alternative UPF1 transcripts were identified in two pancreatic ASC samples. Alternative splicing events caused by one mutation cluster eliminated part of the RNA helicase domain required for UPF1 function, whereas the other cluster of mutations led to elimination of regulatory phosphorylation sites essential for NMD, suggesting that these may be loss-of-function mutations. Consistent with these observations, loss of UPF1 expression was observed in many ASC tumors, in some cases due to biallelic mutations, and NMD substrates were elevated in ASC tumors compared with adjacent normal pancreatic tissue. In addition to identifying a potential tumorigenic role of selective mutations in an NMD gene, these findings suggest that UPF1 mutations and defective NMD may facilitate the diagnosis of pancreatic ASC.
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