BACKGROUND & AIMS: The functional abrogation of several tumor suppressor genes, including p16, DPC4, and p53, is a major mechanism underlying pancreatic ductal carcinogenesis. However, mutational inactivation of these genes is relatively uncommon in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. We hypothesized that an alternative mechanism for gene inactivation (notably, transcriptional silencing by promoter methylation) could be important in the pathogenesis of IPMNs. METHODS: Using methylation-specific polymerase chain reaction, we analyzed the methylation status of 7 CpG islands previously identified as aberrantly methylated in pancreatic adenocarcinoma (including preproenkephalin [ppENK], p16, and thrombospondin 1) in 51 IPMNs of different histologic grades. The relationship between methylation status and expression was evaluated using reverse-transcription polymerase chain reaction for ppENK and immunohistochemistry for p16. RESULTS: We found that more than 80% of the IPMNs exhibited hypermethylation of at least one of these CpG islands. Hypermethylation of ppENK and p16 was detected at a significant higher frequency in high-grade (in situ carcinoma) IPMNs than in low-grade (adenoma/borderline) IPMNs (ppENK, 82% vs. 28%, P = 0.0002; p16, 21% vs. 0%, P = 0.04). Furthermore, the average number of methylated loci was significantly higher in high-grade IPMNs than in low-grade IPMNs (2.4 vs. 0.9; P = 0.0008). Aberrant methylation of ppENK and p16 was associated with loss of expression. CONCLUSIONS: These results suggest that de novo methylation of multiple CpG islands is one of the critical pathways that contributes to the malignant progression of IPMNs.
BACKGROUND & AIMS: The functional abrogation of several tumor suppressor genes, including p16, DPC4, and p53, is a major mechanism underlying pancreatic ductal carcinogenesis. However, mutational inactivation of these genes is relatively uncommon in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. We hypothesized that an alternative mechanism for gene inactivation (notably, transcriptional silencing by promoter methylation) could be important in the pathogenesis of IPMNs. METHODS: Using methylation-specific polymerase chain reaction, we analyzed the methylation status of 7 CpG islands previously identified as aberrantly methylated in pancreatic adenocarcinoma (including preproenkephalin [ppENK], p16, and thrombospondin 1) in 51 IPMNs of different histologic grades. The relationship between methylation status and expression was evaluated using reverse-transcription polymerase chain reaction for ppENK and immunohistochemistry for p16. RESULTS: We found that more than 80% of the IPMNs exhibited hypermethylation of at least one of these CpG islands. Hypermethylation of ppENK and p16 was detected at a significant higher frequency in high-grade (in situ carcinoma) IPMNs than in low-grade (adenoma/borderline) IPMNs (ppENK, 82% vs. 28%, P = 0.0002; p16, 21% vs. 0%, P = 0.04). Furthermore, the average number of methylated loci was significantly higher in high-grade IPMNs than in low-grade IPMNs (2.4 vs. 0.9; P = 0.0008). Aberrant methylation of ppENK and p16 was associated with loss of expression. CONCLUSIONS: These results suggest that de novo methylation of multiple CpG islands is one of the critical pathways that contributes to the malignant progression of IPMNs.
Authors: Tatsuo Hata; Marco Dal Molin; Seung-Mo Hong; Koji Tamura; Masaya Suenaga; Jun Yu; Hiraku Sedogawa; Matthew J Weiss; Christopher L Wolfgang; Anne Marie Lennon; Ralph H Hruban; Michael G Goggins Journal: Clin Cancer Res Date: 2017-02-01 Impact factor: 12.531
Authors: Audrey Vincent; Noriyuki Omura; Seung-Mo Hong; Andrew Jaffe; James Eshleman; Michael Goggins Journal: Clin Cancer Res Date: 2011-05-24 Impact factor: 12.531
Authors: Seung-Mo Hong; David Kelly; Margaret Griffith; Noriyuki Omura; Ang Li; Chung-Pin Li; Ralph H Hruban; Michael Goggins Journal: Mod Pathol Date: 2008-09-26 Impact factor: 7.842
Authors: Frank Schönleben; Wanglong Qiu; Helen E Remotti; Werner Hohenberger; Gloria H Su Journal: Langenbecks Arch Surg Date: 2008-02-21 Impact factor: 3.445