Breast cancer metastasis suppressor-1 promoter methylation in cell-free DNA provides prognostic information in non-small cell lung cancer

Abstract

Background:Breast-cancer metastasis suppressor 1 (BRMS1) gene encodes for a predominantly nuclear protein that differentially regulates the expression of multiple genes, leading to suppression of metastasis without blocking orthotropic tumour growth. The aim of the present study was to evaluate for the first time the prognostic significance of BRMS1 promoter methylation in cell-free DNA (cfDNA) circulating in plasma of non-small cell lung cancer (NSCLC) patients. Towards this goal, we examined the methylation status of BRMS1 promoter in NSCLC tissues, matched adjacent non-cancerous tissues and corresponding cfDNA as well as in an independent cohort of patients with advanced NSCLC and healthy individuals.Methods:Methylation of BRMS1 promoter was examined in 57 NSCLC tumours and adjacent non-cancerous tissues, in cfDNA isolated from 48 corresponding plasma samples, in cfDNA isolated from plasma of 74 patients with advanced NSCLC and 24 healthy individuals.Results:The BRMS1 promoter was highly methylated both in operable NSCLC primary tissues (59.6%) and in corresponding cfDNA (47.9%) but not in cfDNA from healthy individuals (0%), while it was also highly methylated in cfDNA from advanced NSCLC patients (63.5%). In operable NSCLC, Kaplan–Meier estimates were significantly different in favour of patients with non-methylated BRMS1 promoter in cfDNA, concerning both disease-free interval (DFI) (P=0.048) and overall survival (OS) (P=0.007). In advanced NSCLC, OS was significantly different in favour of patients with non-methylated BRMS1 promoter in their cfDNA (P=0.003). Multivariate analysis confirmed that BRMS1 promoter methylation has a statistical significant influence both on operable NSCLC patients' DFI time and OS and on advanced NSCLC patients' PFS and OS.Conclusions:Methylation of BRMS1 promoter in cfDNA isolated from plasma of NSCLC patients provides important prognostic information and merits to be further evaluated as a circulating tumour biomarker.

Circulating tumor DNA: a promising biomarker in the liquid biopsy of cancer

“…Early studies showed that ctDNA possessed many cancer-associated molecular characteristics, such as single-nucleotide mutations [25–29], methylation changes [30–33] and cancer-derived viral sequences [34–36], and therefore were considered to be derived from tumor tissue. These findings were significant for the development of future ctDNA detection technology [37–40].…”

Gene expression profiling and DNA methylation analyses of CTCs

“…BRMS1 promoter was found to be highly methylated in CTC, while immunofluorescence studies in the same cytospins have shown that it was down regulated at the protein level in CTC as well (Chimonidou et al., 2013b). Moreover, we have recently shown that methylation of BRMS1 promoter in circulating tumor DNA isolated from plasma of NSCLC patients provides important prognostic information and merits to be further evaluated as a circulating tumor biomarker (Balgkouranidou et al., 2014).…”

BRMS1L suppresses breast cancer metastasis by inducing epigenetic silence of FZD10

“…SIN3 proteins can link HDAC and co-repressors to chromatin-bound transcription factors to inhibit target gene expression 9,10 . Downregulation of breast cancer metastasis suppressor 1 (BRMS1), a major co-repressor interacting with Sin3A, is associated with metastasis of multiple types of malignancies, including breast, nasopharyngeal, melanoma, non-small-cell lung cancinomas and melanomas [11][12][13][14][15] . Moreover, transfection of BRMS1 into highly metastatic human breast cancer cell lines significantly inhibited lung metastasis in xenografted mice without influencing orthotopic tumour incidence and growth rate, suggesting that BRMS1 is a metastasis suppressor 16 .…”