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Promoter methylation profile in preneoplastic and neoplastic gallbladder lesions
Author(s) -
García Patricia,
Manterola Carlos,
Araya Juan Carlos,
Villaseca Miguel,
Guzmán Pablo,
Sanhueza Antonio,
Thomas Melanie,
Alvarez Héctor,
Roa Juan Carlos
Publication year - 2009
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20457
Subject(s) - biology , methylation , metaplasia , gallbladder , carcinogenesis , carcinoma , dna methylation , epigenetics , intestinal metaplasia , gallbladder cancer , cancer research , cancer , pathology , carcinoma in situ , gastroenterology , gene , medicine , genetics , gene expression
Gallbladder carcinoma (GBC) is a highly malignant neoplasm and represents the leading cause of cancer death in Chilean women. In order to determine the potential role of promoter methylation in gallbladder carcinogenesis, we investigated the frequency of this epigenetic mechanism by methylation‐specific polymerase chain reaction (MSP) in 35 chronic cholecystitis (CC, separated according to the presence or absence of metaplasia), 19 early cancers (mucosa or muscularis propia invasion) and 48 advanced carcinomas with invasion of the gallbladder subserosa (25 cases) and serosa (23 cases). We examined 14 genes and observed an increase of multigenic methylation during tumoral progression which was not significantly associated with the patient's age. Four genes ( DAPK1 , DLC1 , TIMP3 , and RARβ2 ) displayed a progressive increase in their methylation status from CC without metaplasia to advanced carcinoma invading the serosa layer ( P ≤ 0.05). The survival analysis indicated that a methylated condition of DLC1 gene is significantly associated with poor prognosis ( P = 0.04), whereas a methylated state of MGMT gene correlated with better patient survival ( P = 0.006). Our findings indicate that aberrant hypermethylation of promoter regions is an early, progressive and cumulative event in gallbladder carcinogenesis. Furthermore, the methylation levels seems to accumulate in the progression of CC without metaplasia to CC with metaplasia, a fact that could provide new evidence to consider this morphological adaptation of GB mucosa as a premalignant lesion. Finally, the methylation status of some individual genes could be useful biomarkers with potential clinical application in diagnosis or prognosis of GBC if they are validated in a greater number of clinical samples. © 2008 Wiley‐Liss, Inc.