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Mapping Geographic Zones of Cancer Risk with Epigenetic Biomarkers in Normal Breast Tissue

Authors' Affiliations: ¹ Division of Human Cancer Genetics and ² Department of Hematology and Oncology, Comprehensive Cancer Center, and ³ Department of Pathology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio; ⁴ Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; ⁵ Department of Pathology, University of Cambridge, Division of Molecular Histopathology, Addenbrooks' Hospital, Cambridge, United Kingdom; ⁶ Department of Life Science and Institute of Molecular Biology, National Chung-Cheng University, Chia-Yi, Taiwan; and ⁷ Genome Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio

Requests for reprints: Tim H.-M. Huang, Human Cancer Genetics Program, The Ohio State University, Room 514, 420 West 12th Avenue, Columbus, OH 43210. Phone: 614-688-8277; Fax: 614-292-5995; E-mail: tim.huang{at}osumc.edu.

Purpose: Genetic alterations were previously identified in normal epithelia adjacent to invasive cancers. The aim of this study was to determine DNA methylation in histologically normal tissues from multiple geographic zones adjacent to primary breast tumors.

Experimental Design: First, methylation status of a 4-kb region of RASSF1A promoter was interrogated using oligonucleotide-based microarray in 144 samples (primary tumors, 47; adjacent normals, 69; reduction mammoplasty tissues, 28). Second, allelic imbalance (AI)/loss of heterozygosity (LOH) surrounding RASSF1A promoter were analyzed in 30 samples (tumors, 8; adjacent normals, 22). Third, global methylation screening of 49 samples (tumors, 12; adjacent normals, 25; reduction mammoplasty, 12) was done by differential methylation hybridization. Real-time quantitative methylation-specific PCR was used to validate the microarray findings.

Results: DNA methylation in the core RASSF1A promoter was low in reduction mammoplasty tissues (P = 0.0001) when compared with primary tumors. The adjacent normals had an intermediate level of methylation. The regions surrounding the core were highly methylated in all sample types. Microsatellite markers showed AI/LOH in tumors and some of the adjacent normals. Concurrent AI/LOH and DNA methylation in RASSF1A promoter occurred in two of six tumors. Global methylation screening uncovered genes more methylated in adjacent normals than in reduction mammoplasty tissues. The methylation status of four genes was confirmed by quantitative methylation-specific PCR.

Conclusions: Our findings suggest a field of methylation changes extending as far as 4 cm from primary tumors. These frequent alterations may explain why normal tissues are at risk for local recurrence and are useful in disease prognostication.

Commentary

Epigenetic Biomarkers and Breast Cancer: Cause for Optimism

Kala Visvanathan, Saraswati Sukumar, and Nancy E. Davidson
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