Aberrant methylation of Reprimo correlates with genetic instability and predicts poor prognosis in pancreatic ductal adenocarcinoma

Cancer. 2006 Jul 15;107(2):251-7. doi: 10.1002/cncr.21977.


Background: The p53-dependent G2/M checkpoint plays a key role in the maintenance of genomic integrity, thereby protecting cells from neoplastic progression. Reprimo, a gene involved in the p53-induced G2 cell cycle arrest, has been recently identified as a novel target for aberrant methylation in pancreatic and other cancers. The biological and clinical relevance of Reprimo methylation in pancreatic cancer was investigated.

Methods: The methylation status of Reprimo CpG island was analyzed by methylation-specific polymerase chain reaction in a large series of pancreatic cancers and was correlated with p53 mutation status, genetic instability (as measured by the fractional allelic loss), and clinicopathologic features.

Results: Aberrant methylation of Reprimo was identified in 60% (75 of 125) of pancreatic cancer xenografts and primary pancreatic adenocarcinomas. Reprimo methylation was also detectable in 30% (19 of 63) of pancreatic intraepithelial neoplasias (PanIN), known precursors to infiltrating carcinoma. Reprimo methylation was unrelated to the p53 mutation status and associated with the increased degree of genetic instability (P = .04). Furthermore, we found that patients with Reprimo methylation in their primary pancreatic cancers have significantly worse prognosis than those without Reprimo methylation (P = .007). In contrast, other methylation targets in pancreatic cancers (SPARC and CXCR4) did not correlate with prognosis.

Conclusions: These results suggest that aberrant methylation of Reprimo is a common event in pancreatic carcinogenesis and is associated with genetic instability and unfavorable outcome after surgical resection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Carcinoma, Pancreatic Ductal / diagnosis*
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Cycle Proteins / genetics*
  • Chromosomal Instability*
  • CpG Islands
  • DNA Methylation*
  • Glycoproteins / genetics*
  • Humans
  • Mutation
  • Pancreatic Neoplasms / diagnosis*
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology
  • Prognosis
  • Tumor Suppressor Protein p53 / genetics


  • Cell Cycle Proteins
  • Glycoproteins
  • RPRM protein, human
  • Tumor Suppressor Protein p53