Abstract
Aberrant DNA methylation is critical for development and progression of breast cancer. We investigated the association of CpG island methylation in candidate genes and clinicopathological features in 65 African-American (AA) and European-American (EA) breast cancer patients. Quantitative methylation analysis was carried out on bisulfite modified genomic DNA and sequencing (pyrosequencing) for promoter CpG islands of p16, ESR1, RASSF1A, RARβ2, CDH13, HIN1, SFRP1 genes and the LINE1 repetitive element using matched paired non-cancerous and breast tumor specimen (32 AA and 33 EA women). Five of the genes, all known tumor suppressor genes (RASSF1A, RARβ2, CDH13, HIN1 and SFRP1), were found to be frequently hypermethylated in breast tumor tissues but not in the adjacent non-cancerous tissues. Significant differences in the CDH13 methylation status were observed by comparing DNA methylation between AA and EA patients, with more obvious CDH13 methylation differences between the two patient groups in the ER- disease and among young patients (age<50). In addition, we observed associations between CDH13, SFRP1, and RASSF1A methylation and breast cancer subtypes and between SFRP1 methylation and patient's age. Furthermore, tumors that received neoadjuvant therapy tended to have reduced RASSF1A methylation when compared with chemotherapy naïve tumors. Finally, Kaplan Meier survival analysis showed a significant association between methylation at 3 loci (RASSF1A, RARβ2 and CDH13) and reduced overall disease survival. In conclusion, the DNA methylation status of breast tumors was found to be significantly associated with clinicopathological features and race/ethnicity of the patients.
Highlights
Breast cancer is the most commonly diagnosed cancer among women in the United States, with .130,000 cases diagnosed yearly [1]
We evaluated the DNA methylation status for a panel of genes in paired adjacent non-cancerous and breast tumor specimens from a total of 65 patients (32 AA and 33 European American (EA) women)
To further examine the relationship between the methylation profile with patient characteristics and tumor markers, we focused on the 4 genes (RASSF1A, RARb2, CDH13 and SFRP1) that showed the highest relative changes in tissue methylation status across the 65 tissue pairs
Summary
Breast cancer is the most commonly diagnosed cancer among women in the United States, with .130,000 cases diagnosed yearly [1]. Genomic alterations that impact the expression patterns of individual genes or entire signatures in breast cancer have been described and include; inherited BRCA1 and BRCA2 [16], p53 [17], and H-ras mutations [18] and overexpression of cyclin D1 [19]. Some of these genetic alterations tend to occur more commonly in tumors of AA than EA patients as shown for p53 and BRCA1/2 mutations [20,21]. Loo and coworkers observed significant differences in genomic copy number alterations in triple negative tumors from AA and EA women [22], whereas other investigators have reported differences in the gene expression profiles between AA and EA tumors in pathways related to tumor angiogenesis and chemotaxis [23]
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