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Application of a Comprehensive Molecular Assessment for Early-Stage Breast Cancer Patients
a Division of Surgical Oncology, Columbia University Medical Center, New York, New York 10032, USA b Joyce Eisenberg-Keefer Breast Center, John Wayne Cancer Institute, Santa Monica, California 90404, USA c Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California 90404, USA d Department of Skeletal Biology, John Wayne Cancer Institute, Santa Monica, California 90404, USA e Institute of Tumor Biology, University Hospital Hamburg-Eppendorf, Hamburg D-20246, Germany
Key Words: methylation • breast cancer • bone marrow
Address for correspondence: Dr. Dave S.B. Hoon, Department of Molecular Oncology, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404. Voice: 310-449-5267; fax: 310-449-5282. e-mail: Hoon{at}jwci.org
Breast cancer recurrence is a result of undetected metastasis present at the time of primary patient treatment. More sensitive methods are needed to identify subclinical disease progression to better accompany those increasing advances in early breast cancer screening. Aberrant hypermethylation of tumor-suppressor genes is found frequently in primary breast tumors and has been implicated in disease initiation and progression. Epigenetic characterization of tumor cells may provide highly specific and sensitive molecular surrogates for surveillance. We evaluated whether tumor-associated methylated DNA markers could be identified circulating in bone marrow (BM) aspirates and paired serum samples from 33 early-stage patients undergoing surgery for breast cancer. Quantitative methylation-specific PCR (qMSP) was performed using a selected tumor-related gene panel for RAR-ß2, MGMT, RASSF1A, and APC. Tumor-associated hypermethylated DNA was identified in 7 (21%) of 33 BM aspirates and 9 (27%) serum samples. In three patients both BM and serum were positive for hypermethylation. The most frequently detected hypermethylation marker was RASSF1A occurring in 7 (21%) patients. Concordance was present between gene hypermethylation detected in BM or serum samples, and matched-pair primary tumors. Advanced AJCC stage was associated with an increased incidence of circulating gene hypermethylation. In addition, methylation patterns in the sentinel lymph node (SLN) metastasis corresponded with that of the primary tumor, confirming epigenetic clonality is associated with early tumor dissemination. This study demonstrates the novel finding of tumor-associated epigenetic markers in BM aspirates/blood and their potential role as targets for molecular detection.
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