title: DNA methylation index and methylation profile of invasive ductal breast tumors.
abstract: Breast carcinogenesis is a multistep process that involves both genetic and epigenetic alterations. Identification of aberrantly methylated genes in breast tumors and their relation to clinical parameters can contribute to improved diagnostic, prognostic, and therapeutic decision making. Our objective in the present study was to identify the methylation status of 34 cancer-involved genes in invasive ductal carcinomas (IDC). Each of the 70 IDC cases analyzed had a unique methylation profile. The highest methylation frequency was detected in the WT1 (95.7%) and RASSF1 (71.4%) genes. Hierarchical cluster analysis revealed three clusters with different distribution of the prognostic factors tumor grade, lymph node metastasis, and proliferation rate. Methylation of TP73 was associated with high histological grade and high proliferation rate; methylation of RARB was associated with lymph node metastasis. Concurrent methylation of TP73 and RARB was associated with high histological grade, high proliferation rate, increased tumor size, and lymph node metastasis. Patients with more than six methylated genes had higher rates of relapse events and cancer deaths. In multivariate analysis, TP73 methylation and the methylation index were associated with disease outcome. Our results indicate that methylation index and methylation of TP73 and/or RARB are related to unfavorable prognostic factors in patients with IDC. These epigenetic markers should be validated in further studies to improve breast cancer management.
authors.affiliation: Laboratory of Cellular and Molecular Biology, Institute of Histology and Embryology (IHEM-CCT-CONICET), Mendoza, Argentina.
authors.forename: Diego M
authors.initials: DM
authors.lastname: Marzese
authors.forename: Dave S B
authors.initials: DS
authors.lastname: Hoon
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Chong
authors.forename: Francisco E
authors.initials: FE
authors.lastname: Gago
authors.forename: Javier I
authors.initials: JI
authors.lastname: Orozco
authors.forename: Olga M
authors.initials: OM
authors.lastname: Tello
authors.forename: Laura M
authors.initials: LM
authors.lastname: Vargas-Roig
authors.forename: María
authors.initials: M
authors.lastname: Roqué
mesh_terms: D000328:Adult; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D011379:Prognosis; D018168:Receptors, Retinoic Acid / Q000235:genetics; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics; D025721:WT1 Proteins / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D025721:WT1 Proteins; C082925:retinoic acid receptor beta