Abstract Introduction. Inflammatory breast cancer (IBC) is an aggressive form of locally advanced breast cancer with increased 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 hypothesis that the molecular portrait of IBC is a reflection of underlying genomic alterations. Materials and Methods. Mutation and copy number variation (CNV) profiles for 663 genes were assembled from 2.352 publicly available primary tumor samples (subtype distribution: 1.520 HR+, 355 HER2+, 414 TNBC and 190 unassigned) including 127 profiles from patients with IBC. Gene-wise differences in the frequency of genomic aberrations between patients with and without IBC, stratified per subtype, were investigated using Chi-square testing with adjustment for multiple comparisons. Genomic perturbation differences of pathways and processes, represented by KEGG or Gene Ontology gene sets, were evaluated by collapsing mutation and CNV profiles across all genes associated with the respective gene sets. Finally, mutational signature (MS) profiles were calculated and compared between patients with and without IBC. Results. Seventy-six genes showed evidence of more 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. Genes mutated in more than 15% (range 16.2% - 63,5%) of the IBC samples include: AXIN1, ERBB2, ERBB3, CBL, CTNNB1, CYP2D6, FGFR1, INSR, KIT, KMT2A, LRP1B, MYC, PBRM1, SACS, SMAD4, TP53 and ZNF217. Analysis of MS profiles revealed differences for signature 1 (i.e. age-related deamination of 5-methylcytosine), 2 (i.e. APOBEC3 activity), 3 (i.e. defective homologuous recombination), 11 (i.e. alkylating agents), 20 (i.e. DNA mismatch repair) and 24 (i.e. aflatoxin), of which MS 11 and 24 are more active in IBC. When evaluating the same panel of genes in TNBC only, 28 genes were retained, suggesting data are confounded by the subtype distribution. Pathway analysis revealed genomic perturbation of MAPK signaling and chromatin organizational processes in respectively 55% and 74% of TN IBCs. Discussion. These data suggest that IBC is characterized by an extensive mutational burden that results, amongst others in the activation of MAPK signaling as well as chromatin remodeling. The analysis of MS profiles does not provide a clear biological explanation for the increased frequency of genomic alterations in IBC, with APOBEC3 activity, defective homologous recombination, defective DNA mismatch repair and age-related deamination of 5-methylcytosinie all being more prominent in nIBC samples. Notably, the lower frequency of age-related C>T transitions is in line with younger age at diagnosis typical for patients with IBC. Citation Format: Van Laere S, Finetti P, Rypens C, Billet C, Birnbaum D, Vermeulen P, Viens P, Dirix L, Bertucci F. The mutational profile of inflammatory breast cancer reveals a higher mutational burden leading to MAPK activation and chromatin remodeling [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-04-04.