Frameshift mutations of poly(adenosine diphosphate-ribose) polymerase genes in gastric and colorectal cancers with microsatellite instability.

Poly(adenosine diphosphate-ribose) polymerases consist of 16 members that modify nuclear proteins by building adenosine diphosphate-ribose polymers. Poly(adenosine diphosphate-ribose) polymerase 1, the prototype poly(adenosine diphosphate-ribose) polymerase, and some poly(adenosine diphosphate-ribose) polymerases are involved in many cellular processes including DNA damage response/repair, cell death, and inflammation. Inactivation of poly(adenosine diphosphate-ribose) polymerase proteins frequently enhances genomic instability and apoptosis inactivation, suggesting their roles in cancer development. However, genetic alterations of poly(adenosine diphosphate-ribose) polymerase genes have not been reported in cancers. In a public database, we found that poly(adenosine diphosphate-ribose) polymerase 1, poly(adenosine diphosphate-ribose) polymerase 11, poly(adenosine diphosphate-ribose) polymerase 14, poly(adenosine diphosphate-ribose) polymerase 15, tankyrase-1 (TNKS1), and tankyrase-2 (TNKS2) genes have mononucleotide repeats in coding DNA sequences. To see whether these genes are mutated in cancers with microsatellite instability, we analyzed the mononucleotide repeats in 30 gastric cancers with high microsatellite instability, 13 gastric cancers with low microsatellite instability, 45 gastric cancers with stable microsatellite instability, 40 colorectal cancers with high microsatellite instability, 14 colorectal cancers with low microsatellite instability, and 45 colorectal cancers with stable microsatellite instability by single-strand conformation polymorphism. We found poly(adenosine diphosphate-ribose) polymerase 14, TNKS1, and TNKS2 mutations in 8, 4, and 18 cancers, respectively. They were detected in cancers with high microsatellite instability but not in cancers with low microsatellite instability or stable microsatellite instability. The gastric cancers and colorectal cancers with high microsatellite instability harbored one or more mutations of the poly(adenosine diphosphate-ribose) polymerase genes in 50.0% and 27.5%, respectively. Of the genes with mutations, we analyzed poly(adenosine diphosphate-ribose) polymerase 14 protein expression in gastric and colorectal cancers with high microsatellite instability. Loss of poly(adenosine diphosphate-ribose) polymerase 14 expression was observed in 33% of the gastric cancers and 35% of the colorectal cancers with high microsatellite instability, whereas its loss was observed in 31% of the gastric cancers and 36% of the colorectal cancers with low microsatellite instability/stable microsatellite instability. Our data indicate that frameshift mutations of poly(adenosine diphosphate-ribose) polymerases genes and losses of expression of poly(adenosine diphosphate-ribose) polymerase 14 protein are features of gastric and colorectal cancers with high microsatellite instability and suggest that these alterations might contribute to development of cancers with high microsatellite instability by deregulating poly(adenosine diphosphate-ribose) polymerase-mediated signaling.