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.

Aberrant DNA Methylation in Breast Cancer Cells

“…In addition, within patient subgroups that share the same tumor type, one finds differences in morbidity and mortality. It has been proposed that each tumor presents a unique epigenetic signature [11]. Thus, the differences are not only restricted to occur between populations of different geographic regions, but also among individuals of the same population, which supports the validity of the new paradigm of individualized medicine.…”

“…However, some controversial observations have appeared regarding the observed methylation frequencies in distinct genes and their transcriptional impact. When considering breast cancer, for example, some authors report methylation [11,21] with reduced expression of WT1 [21], while others communicate overexpression of this gene in the same tumor types [22]. Interestingly, some publications indicate methylation frequencies in this gene, which are highly different from those communicated by authors in other geographical regions [23].…”

“…Moelans et al [25] found in breast cancer invasive ductal carcinomas of Dutch patients that MSH6 was the most frequently methylated gene. By using the same methodology and studying the same CpG islands on invasive ductal carcinomas of Argentinian patients, our group detected WT1 as the most frequently methylated gene [11]. Thus, in epigenetic studies, the environments (i.e.…”

“…Prognostic markers for breast cancer are of high interest because of the wide variety in outcome of the disease. Aberrant methylation of specific genes has been associated with prognosis [8], response to treatment [9], survival [10], lymph node affection [11] and general outcome [12] in breast cancer. Based on this observation, many efforts have been made over the last few years to establish prognostic, predictive and monitoring markers for breast cancer, including the detection of epigenetically marked, circulating tumor DNA [13,14].…”

Promoter Methylation Status of the Retinoic Acid Receptor-Beta 2 Gene in Breast Cancer Patients: A Case Control Study and Systematic Review

“…In developing countries including Iran, patients diagnosed with breast cancer are 10 years younger compared to those in developed countries [3]. Both genetic and epigenetic changes are involved in the individual susceptibility to breast cancer [5]. Epigenetic modifications alter gene expression through DNA hypermethylation, histone modification, and microRNA mechanisms [6].…”