Abstract
BackgroundIn breast cancer (BC), deregulation of DNA methylation leads to aberrant expressions and functions of key regulatory genes. In our study, we investigated the relationship between the methylation profiles of genes associated with cancer invasivity and clinico-pathological parameters. In detail, we studied differences in the methylation levels between BC patients with haematogenous and lymphogenous cancer dissemination.MethodsWe analysed samples of primary tumours (PTs), lymph node metastases (LNMs) and peripheral blood cells (PBCs) from 59 patients with sporadic disseminated BC. Evaluation of the DNA methylation levels of six genes related to invasivity, ADAM23, uPA, CXCL12, TWIST1, SNAI1 and SNAI2, was performed by pyrosequencing.ResultsAmong the cancer-specific methylated genes, we found lower methylation levels of the SNAI2 gene in histologic grade 3 tumours (OR = 0.61; 95% CI, 0.39–0.97; P = 0.038) than in fully or moderately differentiated cancers. We also evaluated the methylation profiles in patients with different cancer cell dissemination statuses (positivity for circulating tumour cells (CTCs) and/or LNMs). We detected the significant association between reduced DNA methylation of ADAM23 in PTs and presence of CTCs in the peripheral blood of patients (OR = 0.45; 95% CI, 0.23–0.90; P = 0.023).ConclusionThe relationships between the decreased methylation levels of the SNAI2 and ADAM23 genes and cancer de-differentiation and haematogenous dissemination, respectively, indicate novel functions of those genes in the invasive processes. After experimental validation of the association between the lower values of SNAI2 and ADAM23 methylation and clinical features of aggressive BCs, these methylation profiles could improve the management of metastatic disease.
Highlights
In breast cancer (BC), deregulation of DNA methylation leads to aberrant expressions and functions of key regulatory genes
In our previous study of methylation profiles in 206 BC patients we showed that the risk for lymph node metastases (LNMs) development and higher proliferation of cancer cells was increased by hypermethylation of CXC motif ligand 12 (CXCL12) and ADAM23 genes, respectively [17]
DNA methylation in various sample types in BC patients and controls In this study, we evaluated specific DNA methylation levels by the quantitative pyrosequencing method in three types of samples isolated from 59 BC patients, namely, in Primary tumour (PT) and LNM tissues and peripheral blood cells (PBCs)
Summary
In breast cancer (BC), deregulation of DNA methylation leads to aberrant expressions and functions of key regulatory genes. We studied differences in the methylation levels between BC patients with haematogenous and lymphogenous cancer dissemination. It was observed that of 13,785 BC patients undergoing adjuvant chemotherapy, 24.4% developed metastatic disease, with median survival of 20 months. In contrast to previous studies, no general improvement of survival in metastatic recurrent BC patients after chemotherapy has been evidenced over the last three decades [2]. It is generally accepted that during the initiation and progression of cancer, deregulation of epigenetic processes, including DNA methylation, occurs and results in aberrant expression and function of a number of key regulatory genes [3, 4]. Changes in DNA methylation in primary tumours (PTs) compared with normal breast tissues have been partially identified by numerous researchers; whole-genome bisulfite sequencing technology is available, which allows the comprehensive analysis of normal and BC methylomes [5]
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