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  • Author: Wendy W J de Leng x
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Marijn A Vermeulen, Carolien H M van Deurzen, Shusma C Doebar, Wendy W J de Leng, John W M Martens, Paul J van Diest and Cathy B Moelans

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.

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Cathy B Moelans, Joep de Ligt, Petra van der Groep, Pjotr Prins, Nicolle J M Besselink, Marlous Hoogstraat, Natalie D ter Hoeve, Miangela M Lacle, Robert Kornegoor, Carmen C van der Pol, Wendy W J de Leng, Ellis Barbé, Bert van der Vegt, John Martens, Peter Bult, Vincent T H B M Smit, Marco J Koudijs, Isaac J Nijman, Emile E Voest, Pier Selenica, Britta Weigelt, Jorge S Reis-Filho, Elsken van der Wall, Edwin Cuppen and Paul J van Diest

Male breast cancer (MBC) is extremely rare and accounts for less than 1% of all breast malignancies. Therefore, clinical management of MBC is currently guided by research on the disease in females. In this study, DNA obtained from 45 formalin-fixed paraffin-embedded (FFPE) MBCs with and 90 MBCs (52 FFPE and 38 fresh-frozen) without matched normal tissues was subjected to massively parallel sequencing targeting all exons of 1943 cancer-related genes. The landscape of mutations and copy number alterations was compared to that of publicly available estrogen receptor (ER)-positive female breast cancers (smFBCs) and correlated to prognosis. From the 135 MBCs, 90% showed ductal histology, 96% were ER-positive, 66% were progesterone receptor (PR)-positive, and 2% HER2-positive, resulting in 50, 46 and 4% luminal A-like, luminal B-like and basal-like cases, respectively. Five patients had Klinefelter syndrome (4%) and 11% of patients harbored pathogenic BRCA2 germline mutations. The genomic landscape of MBC to some extent recapitulated that of smFBC, with recurrent PIK3CA (36%) and GATA3 (15%) somatic mutations, and with 40% of the most frequently amplified genes overlapping between both sexes. TP53 (3%) somatic mutations were significantly less frequent in MBC compared to smFBC, whereas somatic mutations in genes regulating chromatin function and homologous recombination deficiency-related signatures were more prevalent. MDM2 amplifications were frequent (13%), correlated with protein overexpression (P = 0.001) and predicted poor outcome (P = 0.007). In conclusion, despite similarities in the genomic landscape between MBC and smFBC, MBC is a molecularly unique and heterogeneous disease requiring its own clinical trials and treatment guidelines.