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Distinct Hypermethylation Profile of Primary Breast Cancer Is Associated with Sentinel Lymph Node Metastasis

¹ Department of Molecular Oncology; ² Joyce Eisenberg Keefer Breast Center; Divisions of ³ Biostatistics and ⁴ Surgical Pathology, John Wayne Cancer Institute and Saint John's Health Center, Santa Monica, California

Requests for reprints: Dave Hoon, Department of Molecular Oncology, John Wayne Cancer Institute, 2200 Santa Monica Boulevard, Santa Monica, CA 90404. Phone: 310-449-5267; Fax: 310-449-5282; E-mail: hoon{at}jwci.org.

Purpose: Gene promoter region hypermethylation is a significant event in primary breast cancer. However, its impact on tumor progression and potential predictive implications remain relatively unknown.

Experimental Design: We conducted hypermethylation profiling of 151 primary breast tumors with association to known prognostic factors in breast cancer using methylation-specific PCR for six known tumor suppressor and related genes: RASSF1A, APC, TWIST, CDH1, GSTP1, and RAR-ß2. Furthermore, correlation with sentinel lymph node (SLN) tumor status was assessed as it represents the earliest stage of metastasis that is readily detected. Hypermethylation for any one gene was identified in 147 (97%) of 151 primary breast tumors. The most frequently hypermethylated gene was RASSF1A (81%).

Results: Hypermethylation of the CDH1 was significantly associated with primary breast tumors demonstrating lymphovascular invasion (P = 0.008), infiltrating ductal histology (P = 0.03), and negative for the estrogen receptor (P = 0.005), whereas RASSF1A and RAR-ß2 gene hypermethylation were significantly more common in estrogen receptor–positive (P < 0.001) and human epidermal growth factor receptor 2–positive (P < 0.001) tumors, respectively. In multivariate analysis, hypermethylation of GSTP1 and/or RAR-ß2 was significantly associated with patients having macroscopic SLN metastasis compared with those with microscopic or no sentinel node metastasis (odds ratio, 4.59; 95% confidence interval, 2.02-10.4; P < 0.001). In paired SLN metastasis, CDH1 was the most frequently methylated gene (90%) and provides evidence in patients corroborating its role in the clinical development of metastasis.

Conclusion: Hypermethylation profiling of primary breast tumors is significantly associated with known pathologic prognostic factors and may have additional clinical and pathologic utility for assessing patient prognosis and predicting early regional metastasis.

Key Words: hypermethylation • breast cancer • sentinel lymph node • metastasis

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