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Promoter hypermethylation contributes to TIMP 3 down‐regulation in high stage endometrioid endometrial carcinomas
Author(s) -
Catasus Lluis,
Pons Cristina,
Muñoz Josefina,
Espinosa Iñigo,
Prat Jaime
Publication year - 2013
Publication title -
histopathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.626
H-Index - 124
eISSN - 1365-2559
pISSN - 0309-0167
DOI - 10.1111/his.12047
Subject(s) - methylation , dna methylation , loss of heterozygosity , biology , gene silencing , cancer research , promoter , microsatellite instability , endometrial cancer , immunohistochemistry , gene expression , gene , microbiology and biotechnology , cancer , microsatellite , genetics , immunology , allele
Aims Expression of tissue inhibitor of metalloproteinases‐3 ( TIMP ‐3) has been found to be decreased in several types of cancer by promoter gene hypermethylation. However, little is known regarding the silencing effect of TIMP 3 promoter hypermethylation on gene and protein expression in endometrial carcinomas and its prognostic significance.Methods and resultsTIMP 3 promoter hypermethylation and gene copy number variations were evaluated using a methylation‐specific multiplex ligation‐dependent probe amplification approach in 60 cases of endometrioid endometrial carcinomas. TIMP 3 expression was also evaluated at the transcript and protein levels. Loss of TIMP ‐3 protein expression was found in 44 (73%) of 60 carcinomas. Promoter hypermethylation was identified in 25% (15 of 60); was more frequent in stages II – IV (55%, six of 11) than in stage I (18%, nine of 49; P = 0.021); and was found more commonly in tumours with deep myometrial invasion. MLH 1 and TIMP 3 promoters were hypermethylated simultaneously in the same group of tumours ( P < 0.001). A correlation between TIMP 3 methylation and microsatellite instability ( MSI ) was found ( P = 0.005). TIMP 3 copy number changes were frequently a loss (35%), whereas a gain was detected in only 5%.ConclusionsTIMP 3 promoter hypermethylation was associated with high stage endometrioid endometrial tumours with extrauterine spread. Nevertheless, promoter hypermethylation and loss of heterozygosity are not the only mechanisms for TIMP 3 inactivation.