Promoter methylation of tumor suppressor genes in pre-neoplastic lesions; Potential marker of disease recurrence

Claudia Rengucci, Giulia De Maio, Andrea Casadei Gardini, Mattia Zucca, Emanuela Scarpi, Chiara Zingaretti, Giovanni Foschi, Maria Maddalena Tumedei, Chiara Molinari, Luca Saragoni, Maurizio Puccetti, Dino Amadori, Wainer Zoli, Daniele Calistri

Research output: Contribution to journalArticlepeer-review


Background: Epigenetic alterations of specific genes have been reported to be related to colorectal cancer (CRC) transformation and would also appear to be involved in the early stages of colorectal carcinogenesis. Little data are available on the role of these alterations in determining a different risk of colorectal lesion recurrence. The aim of the present study was to verify whether epigenetic alterations present in pre-neoplastic colorectal lesions detected by colonoscopy can predict disease recurrence. Methods. A retrospective series of 78 adenomas were collected and classified as low (35) or high-risk (43) for recurrence according to National Comprehensive Cancer Network guidelines. Methylation alterations were analyzed by the methylation-specific multiplex ligation probe assay (MS-MLPA) which is capable of quantifying methylation levels simultaneously in 24 different gene promoters. MS-MLPA results were confirmed by pyrosequencing and immunohistochemistry. Results: Higher levels of methylation were associated with disease recurrence. In particular, MLH1, ATM and FHIT gene promoters were found to be significantly hypermethylated in recurring adenomas. Unconditional logistic regression analysis used to evaluate the relative risk (RR) of recurrence showed that FHIT and MLH1 were independent variables with an RR of 35.30 (95% CI 4.15-300.06, P = 0.001) and 17.68 (95% CI 1.91-163.54, P = 0.011), respectively. Conclusions: Histopathological classification does not permit an accurate evaluation of the risk of recurrence of colorectal lesions. Conversely, results from our methylation analysis suggest that a classification based on molecular parameters could help to define the mechanisms involved in carcinogenesis and prove an effective method for identifying patients at high risk of recurrence.

Original languageEnglish
Article number65
JournalJournal of Experimental and Clinical Cancer Research
Issue number1
Publication statusPublished - Aug 5 2014


  • Colorectal adenoma
  • Gene promoter methylation profile
  • Pre-neoplastic lesion classification
  • Prognostic marker
  • Risk of recurrence

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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