title: Promoter hypermethylation contributes to TIMP3 down-regulation in high stage endometrioid endometrial carcinomas.
abstract: OBJECTIVE
  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 TIMP3 promoter hypermethylation on gene and protein expression in endometrial carcinomas and its prognostic significance.
  
  
  RESULTS
  TIMP3 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. TIMP3 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. MLH1 and TIMP3 promoters were hypermethylated simultaneously in the same group of tumours (P < 0.001). A correlation between TIMP3 methylation and microsatellite instability (MSI) was found (P = 0.005). TIMP3 copy number changes were frequently a loss (35%), whereas a gain was detected in only 5%.
  
  
  CONCLUSIONS
  TIMP3 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 TIMP3 inactivation.
authors: Department of Pathology, Hospital de la Santa Creu i Sant Pau, Institute of Biomedical Research, Autonomous University of Barcelona, Barcelona, Spain. lcatasus@santpau.cat
authors: Lluis
authors: L
authors: Catasus
authors: Cristina
authors: C
authors: Pons
authors: Josefina
authors: J
authors: Muñoz
authors: Iñigo
authors: I
authors: Espinosa
authors: Jaime
authors: J
authors: Prat
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D015536:Down-Regulation; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3