Research Papers:

Multigene methylation analysis of enriched circulating tumor cells associates with poor progression-free survival in metastatic breast cancer patients

Theresa Benezeder, Verena Tiran, Alexandra A.N. Treitler, Christoph Suppan, Christopher Rossmann, Herbert Stoeger, Richard J. Cote, Ram H. Datar, Marija Balic and Nadia Dandachi _

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Oncotarget. 2017; 8:92483-92496. https://doi.org/10.18632/oncotarget.21426

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Theresa Benezeder1, Verena Tiran1, Alexandra A.N. Treitler1, Christoph Suppan1, Christopher Rossmann1, Herbert Stoeger1, Richard J. Cote2, Ram H. Datar2, Marija Balic1,3 and Nadia Dandachi1,4

1Medical University of Graz, Department of Internal Medicine, Division of Oncology, Graz, Austria

2University of Miami Miller School of Medicine, Department of Pathology, Miami, Florida, U.S.A.

3Medical University of Graz, Research Unit Circulating Tumor Cells and Cancer Stem Cells, Graz, Austria

4Medical University of Graz, Research Unit Epigenetic and Genetic Cancer Biomarkers, Division of Oncology, Graz, Austria

Correspondence to:

Nadia Dandachi, email: [email protected]

Marija Balic, email: [email protected]

Keywords: circulating tumor cells, enrichment, metastatic breast cancer, methylation, prognosis

Received: April 12, 2017     Accepted: August 27, 2017     Published: September 30, 2017


Blood-based biomarkers such as circulating tumor cells (CTCs) provide dynamic real-time assessment of molecular tumor characteristics beyond the primary tumor. The aim of this study was to evaluate the feasibility of a size-based microfilter to assess multigene methylation analysis of enriched CTCs in a prospective proof-of principle study. We examined the quantitative methylation status of nine genes (AKR1B1, BMP6, CST6, HOXB4, HIST1H3C, ITIH5, NEUROD1, RASSF1, SOX17) in enriched CTCs from metastatic breast cancer patients. Feasibility and clinical performance testing were assessed in a test set consisting of 37 patients and 25 healthy controls. With established cut-off values from the healthy control group, methylation of enriched CTCs was detected in at least one gene in 18/37 patients (48.6%), while 97.8% of all control samples were unmethylated. Patients with CTCs unmethylated for CST6, ITIH5, or RASSF1 showed significantly longer PFS compared to patients with corresponding enriched methylated CTCs. This proof-of-principle study shows the feasibility of a size-based microfilter to enrich and analyze multigene methylation profile of CTCs from metastatic breast cancer patients. For the first time, we report that multigene methylation analysis of enriched CTCs provides prognostic information in metastatic breast cancer patients.

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