TY - JOUR
T1 - The molecular genetic make-up of male breast cancer
AU - Moelans, Cathy B.
AU - de Ligt, Joep
AU - van der Groep, Petra
AU - Prins, Pjotr
AU - Besselink, Nicolle J. M.
AU - Hoogstraat, Marlous
AU - ter Hoeve, Natalie D.
AU - Lacle, Miangela M.
AU - Kornegoor, Robert
AU - van der Pol, Carmen C.
AU - de Leng, Wendy W. J.
AU - Barbé, Ellis
AU - van der Vegt, Bert
AU - Martens, John
AU - Bult, Peter
AU - Smit, Vincent T. H. B. M.
AU - Koudijs, Marco J.
AU - Nijman, Isaac J.
AU - Voest, Emile E.
AU - Selenica, Pier
AU - Weigelt, Britta
AU - Reis-Filho, Jorge S.
AU - van der Wall, Elsken
AU - Cuppen, Edwin
AU - van Diest, Paul J.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Amplification
KW - Breast cancer
KW - Genomic
KW - Male
KW - Mutation f copy number
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85072610514&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31340200
U2 - https://doi.org/10.1530/ERC-19-0278
DO - https://doi.org/10.1530/ERC-19-0278
M3 - Article
C2 - 31340200
SN - 1351-0088
VL - 26
SP - 779
EP - 794
JO - Endocrine-related cancer
JF - Endocrine-related cancer
IS - 10
ER -