title: Promoter methylation of tumor suppressor genes in pre-neoplastic lesions; potential marker of disease recurrence.
abstract: 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.
authors.forename: Claudia
authors.initials: C
authors.lastname: Rengucci
authors.forename: Giulia
authors.initials: G
authors.lastname: De Maio
authors.forename: Andrea
authors.initials: A
authors.lastname: Casadei Gardini
authors.forename: Mattia
authors.initials: M
authors.lastname: Zucca
authors.forename: Emanuela
authors.initials: E
authors.lastname: Scarpi
authors.forename: Chiara
authors.initials: C
authors.lastname: Zingaretti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Foschi
authors.forename: Maria Maddalena
authors.initials: MM
authors.lastname: Tumedei
authors.forename: Chiara
authors.initials: C
authors.lastname: Molinari
authors.forename: Luca
authors.initials: L
authors.lastname: Saragoni
authors.forename: Maurizio
authors.initials: M
authors.lastname: Puccetti
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
authors.forename: Wainer
authors.initials: W
authors.lastname: Zoli
authors.forename: Daniele
authors.initials: D
authors.lastname: Calistri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D057890:Epigenomics; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor
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