Originally published as JCO Early Release 10.1200/JCO.2005.01.3516 on August 14 2006

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Detection of Aberrant Methylation of Four Genes in Plasma DNA for the Detection of Breast Cancer

Mohammad O. Hoque, Qinghua Feng, Papa Toure, Amadou Dem, Cathy W. Critchlow, Stephen E. Hawes, Troy Wood, Carmen Jeronimo, Eli Rosenbaum, Joshua Stern, Mujun Yu, Barry Trink, Nancy B. Kiviat, David Sidransky

From the Department of Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD; Departments of Epidemiology, School of Public Health and Community Medicine, and Pathology, School of Medicine, University of Washington, Seattle, WA; and the Tumor Institute, University of Dakar, Senegal

Address reprint requests to Nancy B. Kiviat, MD, Department of Pathology, Harborview Medical Center, University of Washington, 325 9th Ave, Seattle, WA 98104 e-mail: nbk{at}u.washington.edu; or to David Sidransky, MD, Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, 818 Ross, 720 Rutland Avenue, Baltimore, MD 21205; e-mail: dsidrans{at}jhmi.edu

Purpose: Novel approaches to breast cancer screening are necessary, especially in the developing world where mammography is not feasible. In this study, we explored the hypothesis that blood-based biomarkers have potential for biomarkers for breast cancer.

Patients and Methods: We first determined the frequency of aberrant methylation of four candidate genes (APC, GSTP1, Rassf1A, and RARβ2) in primary breast cancer tissues from West African women with predominantly advanced cancers. We used a high-throughput DNA methylation assay (quantitative methylation-specific polymerase chain reaction) to examine plasma from 93 women with breast cancer and 76 controls for the presence of four methylated genes. Samples were randomly divided evenly into training and validation data sets. Cutoff values for gene positivity of the plasma-based assay and the gene panel were determined by receiver operating characteristic curves in the training data set and subsequently evaluated as a screening tool in the validation data set.

Results: Methylation of at least one gene resulted in a sensitivity of 62% and a specificity of 87%. Moreover, the assay successfully detected 33% (eight of 24) of early-stage tumors.

Conclusion: These data suggest that epigenetic markers in plasma may be of interest for detection of breast cancer. Identification of additional breast cancer specific methylated genes with higher prevalence in early stage cancers would improve this approach.

published online ahead of print at www.jco.org on August 14, 2006.

Supported by received grant support from the National Cancer Institute (National Institutes of Health, Bethesda, MD): 5U01CA 85050, N.B.K.; and U01-CA84986, D.S. Also supported by Oncomethylome Sciences SA.

Under a licensing agreement between Oncomethylome Sciences, SA and the Johns Hopkins University, Dr. Sidransky is entitled to a share of royalty received by the University on sales of products described in this article. Dr. Sidransky owns Oncomethylome Sciences, SA stock, which is subject to certain restrictions under University policy. The term of this arrangement is being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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