The methylation status of cystatin M (CST6) gene in breast tumors was investigated and its prognostic significance as a novel breast cancer biomarker was evaluated. Using methylation-specific PCR (MSP), CST6 promoter methylation was examined in 134 formalin fixed paraffin-embedded tissues (FFPEs): 10 pairs of breast tumors and their surrounding normal tissues, 10 breast fibroadenomas, 11 normal breast tissues and 93 breast tumors. Methylation of CST6 promoter was observed in 2/21 (9.5%) noncancerous breast tissues, 1/10 (10%) benign breast tumors (fibroadenomas) and 52 (55.9%) operable breast cancer tumor samples. CST6 was rarely methylated in the normal tissue surrounding the tumor (10%). During the follow-up period, 24 (25.8%) patients relapsed and 19 (20.4%) died. CST6 methylation was detected in 19 (79.2%) of patients who relapsed and in 15 (78.9%) of patients who died. Disease-free-interval (DFI) and overall survival (OS) were significantly associated with CST6 promoter methylation (p 5 0.004 and p 5 0.001 respectively). Multivariate analysis revealed that CST6 methylation is an independent prognostic factor for DFI (HR 5 3.484; 95% CI: 1.155-10.511; p 5 0.027). and OS (HR 5 9.190; 95% CI: 1.989-42.454; p 5 0.004). CST6 promoter methylation status in tumor cells seems to provide important prognostic information in operable breast cancer and merits to be further evaluated and validated in a larger cohort of patients. ' 2009 UICC

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 orthotopic tumor 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: BRMS1 promoter methylation was examined in 57 NSCLC tumors 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: BRMS1 promoter was highly methylated both in operable NSCLC primary tissues (59.6%) and 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 favor of patients with non-methylated BRMS1 promoter in cfDNA, concerning both DFI (p=0.048) and 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: BRMS1 promoter methylation in cfDNA isolated from plasma of NSCLC patients provides important prognostic information and merits to be further evaluated as a circulating tumor biomarker. Citation Format: Ioanna Balkouranidou, Maria Chimonidou, Georgia Milaki, Emily Tsaroucha, Stelios Kakolyris, Danny Welch, Vasilis Georgoulias, Evi Lianidou. Breast cancer metastasis suppressor-1 promoter methylation in cell free DNA provides prognostic information in non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3826. doi:10.1158/1538-7445.AM2014-3826

Early detection and precise diagnosis of lung cancer are critical to select proper therapeutic treatments as early as possible. Toward this direction, the discovery and exploitation of novel innovative, non-invasive, and reliable tumor biomarkers are of vital importance. In this review, we present emerging blood-based molecular biomarkers that have been evaluated for the detection and monitoring of lung cancer. We specially focus on biomarkers based on a non-invasive liquid biopsy approach, such as circulating tumor cells (CTCs), circulating miRNAs, gene promoter methylation, and DNA mutations in cell-free circulating DNA.

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