title: Methylation profiles of endometrioid and serous endometrial cancers.
abstract: Promoter methylation is a gene- and cancer type-specific epigenetic event that plays an important role in tumour development. As endometrioid (endometrioid endometrial carcinoma, EEC) and serous endometrial cancers (uterine papillary serous carcinoma, UPSC) exhibit different clinical, histological and molecular genetic characteristics, we hypothesized that these differences may be reflected in epigenetic phenomena as well. Identification of a panel of methylation biomarkers could be helpful in a correct histological classification of these two subtypes, which solely on the basis of morphology is not always easy. Methylation-specific multiplex ligation-dependent probe amplification was used to assess the extent of promoter methylation of different tumour suppressor genes in EEC and UPSC. Methylation results were correlated with histology and survival. The median cumulative methylation index of all genes was significantly higher in EEC (124) than in UPSC (93) (P<0.001). Promoter methylation of CDH13 and MLH1 was more frequently present in EEC, while CDKN2B and TP73 were more frequently methylated in UPSC. Almost 90% of EEC and 70% of UPSC could be predicted by CDH13 and TP73. In EEC, methylation of MLH1 was associated with a shorter disease-free survival (DFS; P<0.0001) and overall survival (OS; P=0.005). In a multivariate model, MLH1 methylation emerged as an additional prognostic factor to stage for DFS (P=0.002). In conclusion, promoter methylation is more common in EEC than UPSC. A panel of methylation biomarkers could be useful to distinguish between the two histological subtypes of endometrial cancer. Furthermore, methylation of MLH1 may have prognostic value in EEC.
authors.affiliation: Department of Gynaecological Oncology, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands.
authors.forename: Laura M S
authors.initials: LM
authors.lastname: Seeber
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Zweemer
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchionni
authors.forename: Leon F A G
authors.initials: LF
authors.lastname: Massuger
authors.forename: Vincent T H B M
authors.initials: VT
authors.lastname: Smit
authors.forename: W Marchien
authors.initials: WM
authors.lastname: van Baal
authors.forename: René H M
authors.initials: RH
authors.lastname: Verheijen
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific) / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; C036341:DNA modification methylase HpaI; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific)