Home LiteratureArticle Details
PMID: 12000709 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma.

The American journal of pathology ·Vol. 160 ·No. 5 ·2002-05-00 ·Pages 1573-81

Fukushima N, Sato N, Ueki T, Rosty C, Walter KM, Wilentz RE, Yeo CJ, Hruban RH, Goggins M

Abstract

Pancreatic intraductal neoplasia (PanIN) is thought to be the precursor to infiltrating pancreatic ductal adenocarcinoma. We have previously shown that the preproenkephalin (ppENK) and p16 genes are aberrantly methylated in pancreatic adenocarcinoma. In this study we define the methylation status of the ppENK and p16 genes in various grades of PanINs. One hundred seventy-four samples (28 nonneoplastic pancreatic epithelia, 7 reactive epithelia, 29 PanIN-1A, 48 PanIN-1B, 27 PanIN-2, 14 PanIN-3, 15 invasive ductal adenocarcinomas, and 6 miscellaneous pancreatic neoplasms) were microdissected from 29 formalin-fixed paraffin-embedded surgically resected pancreata, and were analyzed by methylation-specific polymerase chain reaction. Fourteen of 15 (93.3%) invasive pancreatic ductal adenocarcinomas showed methylation of the ppENK gene and 4 of 15 (26.7%) showed methylation of the p16 gene. Nonneoplastic pancreatic epithelia did not harbor methylation of either gene. The prevalence of methylation of the ppENK gene increased significantly with increasing PanIN grade. A similar nonsignificant trend was noted for p16 methylation. Aberrant methylation of the ppENK gene was found in 7.7% of PanIN-1A, 7.3% of PanIN-1B, 22.7% of PanIN-2, and 46.2% of PanIN-3. Aberrant methylation of the p16 gene was found in 12% of PanIN-1A, 2.6% of PanIN-1B, 4.5% of PanIN-2, and 21.4% of PanIN-3. All but one of the PanINs from the 14 pancreata without pancreatic carcinoma was unmethylated with respect to either the p16 or ppENK gene. Our results suggest that methylation-related inactivation of the ppENK and p16 genes is an intermediate or late event during pancreatic carcinogenesis. Because aberrant methylation of ppENK or p16 was more often detected in similar grade PanINs from patients with pancreatic carcinoma than in those with other pancreatic diseases, it may be a useful indicator of the potential malignancy of epithelial cells of the pancreas.

MeSH Terms
Aged Aged, 80 and over Carcinoma, Pancreatic Ductal/genetics,pathology Chronic Disease Cyclin-Dependent Kinase Inhibitor p16/genetics DNA Methylation DNA, Neoplasm/genetics,metabolism Enkephalins/genetics Epithelium/metabolism,pathology Female Humans Male Middle Aged Neoplasm Invasiveness Pancreas/metabolism,pathology Pancreatic Neoplasms/genetics,pathology Pancreatitis/genetics,pathology Protein Precursors/genetics
Chemicals
Cyclin-Dependent Kinase Inhibitor p16 DNA, Neoplasm Enkephalins Protein Precursors preproenkephalin
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Fukushima Noriyoshi
Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2196, USA.
Sato Norihiro
Ueki Takashi
Rosty Christophe
Walter Kimberly M
Wilentz Robb E
Yeo Charles J
Hruban Ralph H
Goggins Michael
References (32)
32 references, click to expand
  1. Accelerated age-related CpG island methylation in ulcerative colitis.
    Cancer Res. 2001 May 1;61(9):3573-7 PMID: 11325821
  2. CpG island methylation in premalignant stages of gastric carcinoma.
    Cancer Res. 2001 Apr 1;61(7):2847-51 PMID: 11306456
  3. Hypermethylation of 14-3-3 sigma (stratifin) is an early event in breast cancer.
    Oncogene. 2001 Jun 7;20(26):3348-53 PMID: 11423985
  4. Age-related hypermethylation of the 5' region of MLH1 in normal colonic mucosa is associated with microsatellite-unstable colorectal cancer development.
    Cancer Res. 2001 Oct 1;61(19):6991-5 PMID: 11585722
  5. p16(INK4a) lesions are common, early abnormalities that undergo clonal expansion in Barrett's metaplastic epithelium.
    Cancer Res. 2001 Nov 15;61(22):8284-9 PMID: 11719461
  6. Identification and characterization of differentially methylated CpG islands in pancreatic carcinoma.
    Cancer Res. 2001 Dec 1;61(23):8540-6 PMID: 11731440
  7. Aberrant promoter methylation of multiple genes in bronchial brush samples from former cigarette smokers.
    Cancer Res. 2002 Jan 15;62(2):351-5 PMID: 11809677
  8. Relation of pancreatic duct hyperplasia to carcinoma.
    Cancer. 1979 Apr;43(4):1418-28 PMID: 445339
  9. CpG methylation inhibits proenkephalin gene expression and binding of the transcription factor AP-2.
    Nucleic Acids Res. 1990 Jul 11;18(13):3975-82 PMID: 1695733
  10. Analysis of K-ras gene mutation in hyperplastic duct cells of the pancreas without pancreatic disease.
    Gastroenterology. 1996 Jan;110(1):227-31 PMID: 8536861
  11. Overexpression of p53 protein in adenocarcinoma of the pancreas.
    Am J Clin Pathol. 1994 Jun;101(6):684-8 PMID: 8209852
  12. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group.
    N Engl J Med. 1993 May 20;328(20):1433-7 PMID: 8479461
  13. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands.
    Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9821-6 PMID: 8790415
  14. p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma.
    Cancer Res. 1997 Jun 1;57(11):2140-3 PMID: 9187111
  15. Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene.
    Cancer Res. 1998 Jun 1;58(11):2339-42 PMID: 9622070
  16. Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression.
    Cancer Res. 1998 Oct 15;58(20):4740-4 PMID: 9788631
  17. Hypermethylation of the CDKN2/p16 promoter during neoplastic progression in Barrett's esophagus.
    Gastroenterology. 1998 Dec;115(6):1381-6 PMID: 9834265
  18. Incidence of cancer in the course of chronic pancreatitis.
    Am J Gastroenterol. 1999 May;94(5):1253-60 PMID: 10235203
  19. Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers.
    Am J Pathol. 1999 Jun;154(6):1835-40 PMID: 10362809
  20. Microsatellite instability in inflamed and neoplastic epithelium in ulcerative colitis.
    J Clin Pathol. 2001 Jul;54(7):526-32 PMID: 11429424
  21. Pancolonic chromosomal instability precedes dysplasia and cancer in ulcerative colitis.
    Cancer Res. 1999 Oct 15;59(20):5148-53 PMID: 10537290
  22. In situ detection of the hypermethylation-induced inactivation of the p16 gene as an early event in oncogenesis.
    Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12754-9 PMID: 10535995
  23. hMLH1 promoter hypermethylation is an early event in human endometrial tumorigenesis.
    Am J Pathol. 1999 Nov;155(5):1767-72 PMID: 10550333
  24. Hypermethylation of multiple genes in pancreatic adenocarcinoma.
    Cancer Res. 2000 Apr 1;60(7):1835-9 PMID: 10766168
  25. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression.
    Cancer Res. 2000 Apr 1;60(7):2002-6 PMID: 10766191
  26. BRCA2 is inactivated late in the development of pancreatic intraepithelial neoplasia: evidence and implications.
    Am J Pathol. 2000 May;156(5):1767-71 PMID: 10793087
  27. Genetic progression in the pancreatic ducts.
    Am J Pathol. 2000 Jun;156(6):1821-5 PMID: 10854204
  28. Opioid growth factor regulates the cell cycle of human neoplasias.
    Int J Oncol. 2000 Nov;17(5):1053-61 PMID: 11029512
  29. ACVR1B (ALK4, activin receptor type 1B) gene mutations in pancreatic carcinoma.
    Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3254-7 PMID: 11248065
  30. p16(INK4a) alterations in chronic pancreatitis-indicator for high-risk lesions for pancreatic cancer.
    Surgery. 2001 Apr;129(4):490-7 PMID: 11283541
  31. Aberrant methylation during cervical carcinogenesis.
    Clin Cancer Res. 2001 Mar;7(3):584-9 PMID: 11297252
  32. Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions.
    Am J Surg Pathol. 2001 May;25(5):579-86 PMID: 11342768
Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.1016/S0002-9440(10)61104-2
Published
2002-05-00
Pages
1573-81
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1850889
Subset
IM
Grants
NCI NIH HHS · P50 CA062924 · United States
NCI NIH HHS · CA62924 · United States
NCI NIH HHS · CA91968 · United States
External Links
PubMed source DOI: 10.1016/S0002-9440(10)61104-2 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2