title: Epigenetic fingerprint in endometrial carcinogenesis: the hypothesis of a uterine field cancerization.
abstract: Transcriptional silencing by CpG island hypermethylation plays a critical role in endometrial carcinogenesis. In a collection of benign, premalignant and malignant endometrial lesions, a methylation profile of a complete gene panel, such steroid receptors (ERα, PR), DNA mismatch repair (hMLH1), tumor-suppressor genes (CDKN2A/P16 and CDH1/E-CADHERIN) and WNT pathway inhibitors (SFRP1, SFRP2, SFRP4, SFRP5) was investigated in order to demonstrate their pathogenetic role in endometrial lesions. Our results indicate that gene hypermethylation may be an early event in endometrial endometrioid tumorigenesis. Particularly, ERα, PR, hMLH1, CDKN2A/P16, SFRP1, SFRP2 and SFRP5 revealed a promoter methylation status in endometrioid carcinoma, whereas SFRP4 showed demethylation in cancer. P53 immunostaining showed weak-focal protein expression level both in hyperplasic lesions and in endometrioid cancer. Non-endometrioid cancers showed very low levels of epigenetic methylations, but strong P53 protein positivity. Fisher exact test revealed a statistically significant association between hMLH1, CDKN2A/P16 and SFRP1 genes methylation and endometrioid carcinomas and between hMLH1 gene methylation and peritumoral endometrium (p < 0.05). Our data confirm that the methylation profile of the peritumoral endometrium is different from the altered molecular background of benign endometrial polyps and hyperplasias. Therefore, our findings suggest that the methylation of hMLH1, CDKN2A/P16 and SFRP1 may clearly distinguish between benign and malignant lesions. Finally, this study assessed that the use of an epigenetic fingerprint may improve the current diagnostic tools for a better clinical management of endometrial lesions.
authors.affiliation: Department of General Pathology, SUN, Naples, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Di Domenico
authors.forename: Angela
authors.initials: A
authors.lastname: Santoro
authors.forename: Carmela
authors.initials: C
authors.lastname: Ricciardi
authors.forename: Mirella
authors.initials: M
authors.lastname: Iaccarino
authors.forename: Stefania
authors.initials: S
authors.lastname: Iaccarino
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Freda
authors.forename: Antonia
authors.initials: A
authors.lastname: Feola
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanguedolce
authors.forename: Simona
authors.initials: S
authors.lastname: Losito
authors.forename: Daniela
authors.initials: D
authors.lastname: Pasquali
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Spiezio Sardo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
authors.forename: Carmine
authors.initials: C
authors.lastname: Nappi
authors.forename: Pantaleo
authors.initials: P
authors.lastname: Bufo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Guida
authors.forename: Gaetano
authors.initials: G
authors.lastname: De Rosa
authors.forename: Alberto
authors.initials: A
authors.lastname: Abbruzzese
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pannone
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011987:Receptors, Steroid; D016159:Tumor Suppressor Protein p53