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Nonrandom Distribution of Aberrant Promoter Methylation of Cancer-Related Genes in Sporadic Breast Tumors

¹ Laboratory of Gene Therapy and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico "Casa Sollievo della Sofferenza," San Giovanni Rotondo (FG), Italy; ² Laboratory of Molecular Medicine and Biotechnology, ³ Department of Pathology, and ⁴ Breast Unit, Department of Surgery, University "Campus BioMedico," Rome, Italy; ⁵ Department of Pathology "L. Armanni" II University of Naples, Naples, Italy; ⁶ Neurobiology and Molecular Medicine Institute, Molecular Medicine Section, Consiglio Nazionale delle Ricerche, Rome, Italy; ⁷ Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and ⁸ Clinical Experimental Oncology Laboratory and Department "Donna," National Cancer Institute, Bari, Italy

ABSTRACT

Purpose: In an effort to additionally determine the global patterns of CpG island hypermethylation in sporadic breast cancer, we searched for aberrant promoter methylation at 10 gene loci in 54 primary breast cancer and 10 breast benign lesions.

Experimental Design: Genomic DNA sodium bisulfate converted from benign and malignant tissues was used as template in methyl-specific PCR for BRCA1, p16, ESR1, GSTP1, TRß1, RARß2, HIC1, APC, CCND2, and CDH1 genes.

Results: The majority of the breast cancer (85%) showed aberrant methylation in at least 1 of the loci tested with half of them displaying 3 or more methylated genes. The highest frequency of aberrant promoter methylation was found for HIC1 (48%) followed by ESR1 (46%), and CDH1 (39%). Similar methylation frequencies were detected for breast benign lesions with the exception of the CDH1 gene (P = 0.02). The analysis of methylation distribution indicates a statistically significant association between methylation of the ESR1 promoter, and methylation at CDH1, TRß1, GSTP1, and CCND2 loci (P < 0.03). Methylated status of the BRCA1 promoter was inversely correlated with methylation at the RARß2 locus (P < 0.03).

Conclusions: Our results suggest a nonrandom distribution for promoter hypermethylation in sporadic breast cancer, with tumor subsets characterized by aberrant methylation of specific cancer-related genes. These breast cancer subgroups may represent separate biological entities with potential differences in sensitivity to therapy, occurrence of metastasis, and overall prognosis.

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