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Ductal carcinoma  in situ  (DCIS) of the male breast is very rare and has hardly been studied molecularly. In males, we compared methylation status of 25 breast cancer-related genes in pure DCIS ( n  = 18) and invasive breast carcinoma (IBC) with adjacent DCIS (DCIS-AIC) ( n  = 44) using methylation-specific multiplex ligation-dependent probe amplification. Results were compared to female breast cancer (BC). There were no significant differences in methylation features between male pure DCIS, DCIS-AIC and IBC after correction for multiple comparisons. In paired analysis of IBC and adjacent DCIS,  CADM1  showed a significantly higher absolute methylation percentage in DCIS ( P  = 0.002). In cluster analysis, two clusters stood out with respectively infrequent and frequent methylation ( GATA5 ,  KLLN ,  PAX6 ,  PAX5 ,  CDH13 ,  MSH6  and  WT1  were frequently methylated). Compared to female DCIS, methylation was in general much less common in male DCIS, especially for  VHL ,  ESR1 ,  CDKN2A ,  CD44 ,  CHFR ,  BRCA2 ,  RB1  and  STK11 . In contrast,  THBS1  and  GATA5  were more frequently methylated in male DCIS. In conclusion, there is frequent methylation of  GATA5 ,  KLLN ,  PAX6 ,  PAX5 ,  CDH13 ,  MSH6  and  WT1  in male DCIS. Since there was little change in the methylation status for the studied genes from pure male DCIS to DCIS-AIC and IBC, methylation of these seven genes is more likely to occur early in male breast carcinogenesis. Based on the current markers male DCIS seems to be an epigenetically more advanced precursor of male BC, although in comparison to its female counterpart it appears that fewer loci harbor methylation, pointing to differences between male and female breast carcinogenesis with regard to the studied loci.

Promoter hypermethylation in ductal carcinoma in situ of the male breast