Frequent codeletion of p16/MTS1 and p15/IWTS2 and genetic alterations in p16/MTS1 in pancreatic tumors

Background & Aims: Cell-cycle inhibitor and tumor-suppressor gene p16/MTS1 was found to be altered in a variety of human tumors. To directly investigate genetic alterations and expression of p16/MTS1 and p15/MTS2, this study surveyed pancreatic tumors. Methods: Cell-cycle inhibitors were analyzed for genetic alterations and expression by polymerase chain reaction, DNA sequencing, reverse-transcription polymerase chain reaction, and Western blotting. Results:The analysis of pancreatic adenocarcinomas (19 cell lines and 3 xenografts) for p16/MTS1 and p15/MTS2 revealed homozygous deletions in 10 of 22 cases (46%) (7 cell lines and 3 xenografts) involving both genes. We show in these 7 cell lines as well as in 3 additional cases (10 of 19 [53%]) loss of p16/MTS2 transcripts and in 2 further cases (12 of 19 [63%]) mutations leading to the loss of p16 protein. The frequency of mutations in p16/MTS2 transcripts was 56% (5 of 9). In contrast to p16/MTS1, p15/MTS2 transcripts were obtained in all cases exhibiting the p15/MTS2 gene (54%). Loss of expression was not observed for p27 and p18. Conclusions: These results support that loss of p16 function could be involved in pancreatic cancer and may explain at least in part the aggressive behavior of this tumor type.