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Ductal carcinoma  in situ  (DCIS) is a non-invasive lesion of the breast that is frequently detected by mammography and subsequently removed by surgery. However, it is estimated that about half of the detected lesions would never have progressed into invasive cancer. Identifying DCIS and invasive cancer specific epigenetic lesions and understanding how these epigenetic changes are involved in triggering tumour progression is important for a better understanding of which lesions are  at risk  of becoming invasive.    Methods  Quantitative DNA methylation analysis of  ABCB1, CDKN2A/p16   INK4a  ,  ESR1, FOXC1, GSTP1, IGF2, MGMT, MLH1, PPP2R2B, PTEN  and  RASSF1A  was performed by pyrosequencing in a series of 27 pure DCIS, 28 small invasive ductal carcinomas (IDCs), 34 IDCs with a DCIS component and 5 normal breast tissue samples.  FOXC1, ABCB1, PPP2R2B  and  PTEN  were analyzed in 23 additional normal breast tissue samples. Real-Time PCR expression analysis was performed for  FOXC1 .    Results  Aberrant DNA methylation was observed in all three diagnosis groups for the following genes:  ABCB1, FOXC1 ,  GSTP1 ,  MGMT, MLH1 ,  PPP2R2B ,  PTEN  and  RASSF1A . For most of these genes, methylation was already present at the DCIS level with the same frequency as within IDCs. For  FOXC1  significant differences in methylation levels were observed between normal breast tissue and invasive tumours ( P  < 0.001). The average DNA methylation levels were significantly higher in the pure IDCs and IDCs with DCIS compared to pure DCIS ( P  = 0.007 and  P  = 0.001, respectively). Real-time PCR analysis of  FOXC1  expression from 25 DCIS, 23 IDCs and 28 normal tissue samples showed lower gene expression levels of  FOXC1  in both methylated and unmethylated tumours compared to normal tissue ( P  < 0.001). DNA methylation levels of  FOXC1, GSTP1, ABCB1  and  RASSF1A  were higher in oestrogen receptor (ER) positive vs. ER negative tumours; whereas methylation levels of  FOXC1, ABCB1, PPP2R2B  and  PTEN  were lower in tumours with a  TP53  mutation.    Conclusions  Quantitative methylation analysis identified  ABCB1, FOXC1, PPP2R2B  and  PTEN  as novel genes to be methylated in DCIS. In particular,  FOXC1  showed a significant increase in the methylation frequency in invasive tumours. Low  FOXC1  gene expression in both methylated and unmethylated DCIS and IDCs indicates that the loss of its expression is an early event during breast cancer progression.

Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer