Abstract
Abstract Background: In breast cancer, promoter CpG island hypermethylation has been described for various genes in all aspects of cellular function. However, most studies focused on the methylation status in tumor-related genes in invasive breast cancer, compared to normal breast tissue, and methylation studies of potential precursor lesions of breast cancer were sparse. We investigated the changes in promoter CpG islands hypermethylation during breast cancer progression from intraductal proliferative lesions [usual ductal hyperplasia (UDH), atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS)] to invasive ductal carcinoma (IDC) of breast, and tried to find the specific changes in each step of tumorigenesis. Materials and Methods: We performed MethyLight analyses for methylation status of 57 CpG island loci in 20 IDCs and its paired normal breast tissues. After selecting 15 CpG island loci showing cancer-specific DNA methylation, another sets of normal breast tissue from non-cancer patients (n=10), UDH (n=10), ADH (n=20), DCIS (n=30) and IDC (n=30) were analyzed for these loci. Results: By this approach, we found six new methylation markers of breast cancer including DLEC1, GRIN2B, HOXA1, MT1G, SFRP4 and TMEFF2, as well as APC, GSTP1, HOXAIO, IGF2, RARB, RASSF1A, RUNX3, SCGB3A1 (HIN-1) and SFRP1. The number of methylated genes showed stepwise increase from normal breast to ducal hyperplasia (DH) and DCIS, while IDC showed no difference with DCIS (median, 1 for normal breast, 2 for DH, 5 for DCIS, 6 for IDC; P<0.001). Of the 15 CpG island loci tested, nine loci already showed methylation in normal breast tissue. Methylation of RASSF1A, DLEC1 and SCGB3A1 (HIN-1) promoter CpG islands was significantly higher in DH than in normal breast tissues. Eight CpG island loci (APC, GRIN2B, GSTP1, HOXA1, RARB, RUNX3, SFRP1 and TMEFF2) showed higher methylation frequency and levels in DCIS compared to DH. DICS and IDC showed no difference in the methylation levels or frequency in the 14 CpG islands except HOXA10. Discussion: Our results indicated that CpG island methylation of tumor-related genes is an early event and accumulate with breast cancer progression. CpG island methylation was significantly changed during the progression of DH to DCIS, and DCIS showed similar CpG island methylation with IDC, suggesting that the transition of DH to DCIS is a critical step for breast cancer tumorigenesis associated with promoter CpG islands hypermethylation. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-04-02.
Published Version
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