Topic:
 
Issue Section:
 Biomarkers, translational research and precision medicine
Background: Inflammatory breast cancer (IBC) is an aggressive form of breast cancer with elevated metastatic potential. In the past, we have identified a gene expression profile that characterizes IBC, suggesting that a specific molecular biology underpins this devastating disease. Here, we explore the genomic alterations underlying IBC.
Methods: Mutation and copy number variation (CNV) profiles for 756 genes were assembled from 2.920 primary tumor samples (subtype distribution: 63% HR+, 18% HER2+, and 19% TNBC) including 101 profiles from patients with IBC before therapy and 468 profiles from metastatic breast cancer samples. Differences in the frequency of genomic aberrations between patients with and without IBC, stratified per subtype, were investigated. Genomic perturbation differences for pathways and mutational signature (MS) profiles were compared between patients with and without IBC.
Results: Seventy-six genes showed evidence of extensive genomic alterations in samples from patients with IBC as compared to those without IBC (i.e. false discovery rate < 10%), whereas only 3 genes reveal the opposite pattern. The 10 top scoring genes according to the odds ratio include: MYC, CYP2D6, VEGFA, CCND1, GNAQ, ZNF703, PTPN11, MCL1, CDK4, and CCDC6. Analysis of MS profiles revealed differences for signature 2, -11, -20, -23 and -24. When comparing to metastatic breast cancer samples, mutations in genes involved in homologuous recombination and in the NOTCH pathway were more prevalent in IBC.
Conclusions: These data suggest that IBC is characterized by an extensive mutational burden that results, amongst others in the activation of NOTCH signaling as well as deficient homologuous recombination. The analysis of MS profiles identifies 3 mutational processes in IBC that are associated with transcriptional strand-bias for mutations involving a cytosine (i.e. C>T and C>A), which is indicative for transcription coupled nucleotide excision repair and suggests that mutations involve the complementary guanine base.
Legal entity responsible for the study: University Antwerp.
Funding: Has not received any funding.
Disclosure: All authors have declared no conflicts of interest.
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