The molecular genetic make-up of male breast cancer

in Endocrine-Related Cancer
Correspondence should be addressed to C B Moelans:
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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.

Downloadable materials

  • Supplementary Table 1. List of 1943 genes included in the targeted capture massively parallel sequencing platform.
  • Supplementary Table 2. Sequencing statistics (SOLID 5500).
  • Supplementary Table 3. Sanger sequencing variants and primer sequences.
  • Supplementary Table 4. List of somatic mutations.
  • Supplementary Table 5. BRCA2 germline mutations within the paired tumor/normal subcohort.
  • Supplementary Table 6. List of the 220 most frequently amplified genes in this study. The table includes their chromosomal location, the amplification frequency in ER-positive female breast cancer with associated p-value for difference in proportions, the preference for surrogate intrinsic molecular subtype, and associations with clinical, pathological and genetic characteristics. Potentially druggable gene categories, clinical actionability and known drug interactions are indicated per gene.
  • Supplementary Table 7. Kaplan Meier and multivariable Cox Regression 5-year overall survival (OS) analysis of 10 frequently amplified genes in MBC.
  • Supplementary Figure 1. Pattern of PIK3CA somatic mutations in male (n=107) versus female breast cancer (n=5284; cBioPortal)(Cerami et al., 2012, Gao et al., 2013).
  • Supplementary Figure 2. PIK3CA mutations predict worse 5-year overall survival in male breast cancer.
  • Supplementary Figure 3. Sanger sequencing confirmation of a selected set of SNVs in HER2 (ERBB2), GATA3, BRCA2 and PIK3CA. Positions and samples are indicated. Not all samples with SNVs at these positions are shown.
  • Supplementary Figure 4. Association of copy number alteration (CNA) load with clinical, pathological and genomic characteristics.
  • Supplementary Figure 5. Association of MDM2 amplifications with clinical, pathological and genomic characteristics.
  • Supplementary Methods. Detailed protocol for DNA isolation and mutation calling.
  • Supplementary Results. Association of mutational load with clinicopathological characteristics, Sanger sequencing validation, and germline mutations in AR, CHEK2 and PALB2 with medium to high predicted impact


      Society for Endocrinology

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    Somatic non-synonymous mutations and recurrent amplifications in 135 male breast cancers. Individual genes are represented as rows, and individual patients are represented as columns. Patients with pathogenic germline BRCA2 mutations or Klinefelter syndrome are indicated, as well as tumor histology and the distribution of surrogate IHC subtype.

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    Comparison of MBC somatic mutation frequencies to METABRIC and TCGA ER-positive FBC. Genes have been sorted per function and 95% CI ( have been indicated. * indicates a significant difference with METABRIC and/or TCGA.

  • View in gallery

    Mutational signature analysis in MBCs compared to ER/HER2- matched FBCs (TCGA). HRD, homologous recombination defect; MMR, mismatch repair

  • View in gallery

    Heatmap of copy number alterations in the male breast cancers following unsupervised hierarchical cluster analysis. Two clusters seem to stand out: the top cluster with many events dominated by luminal A-like tumors and the bottom cluster dominated by luminal B-like cancers. Klinefelter syndrome patients (gray) show few copy number alterations.

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    MDM2 amplification in male breast cancer is associated with poor 5-year overall survival, PR negativity and high tumor grade.


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