The molecular genetic make-up of male breast cancer

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 SelenicaBritta Weigelt, Jorge S. Reis-Filho, Elsken van der Wall, Edwin Cuppen, Paul J. van Diest

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)779-794
JournalEndocrine-Related Cancer
Volume26
Issue number10
DOIs
Publication statusPublished - 2019

Cite this

Moelans, C. B., de Ligt, J., van der Groep, P., Prins, P., Besselink, N. J. M., Hoogstraat, M., ter Hoeve, N. D., Lacle, M. M., Kornegoor, R., van der Pol, C. C., de Leng, W. W. J., Barbé, E., van der Vegt, B., Martens, J., Bult, P., Smit, V. T. H. B. M., Koudijs, M. J., Nijman, I. J., Voest, E. E., ... van Diest, P. J. (2019). The molecular genetic make-up of male breast cancer. Endocrine-Related Cancer, 26(10), 779-794. https://doi.org/10.1530/ERC-19-0278