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Background Epidemiological evidence indicates a clear relationship between pregnancy and breast cancer (BC) risk. However, little is known regarding the impact of pregnancy on BC biology. DNA copy number aberrations (CNAs) play an important role in breast carcinogenesis. BC during pregnancy is a rare disease, however it can be used as a model to study the impact of pregnancy on BC biology. Methods We retrospectively included 54 pregnant and 113 non-pregnant BC patients matched for age and stage with complete clinic-pathological, gene expression and 5-year follow-up data. CNAs were assessed using Affymetrix OncoScan FFPE arrays. First, we filtered genes whose expression was driven by CNAs. Then, we identified genes that were differentially affected by pregnancy both at the CNA and the gene expression level. Results After quality control, CNA profiles were obtained for 38 pregnant and 87 non-pregnant BC patients. There were no significant differences in classical clinic-pathological features (pT, pN, grade, PAM50). We selected 1981 genes whose expression was correlated with CNAs (ρ ≥ 0.4). Among these, 77 genes were altered at the expression level (p ≤ 0.01) between pregnant and control patients, whereas 171 genes were altered at the CNA level (p ≤ 0.05). Twenty-eight genes were concomitantly altered at the expression and CNA levels which was significantly higher than expected (p = 0.021, permutation test). These genes were mapped on three different chromosomes. Genes located on chr7q and chr11q were associated with copy number gains and were up-regulated in pregnant patients whereas genes located on chr22q were associated with copy number loss in control patients. Of interest we identified 6 putative oncogenes (CDK6, ESRRA, S6K2, LIMK2, MKL1) that were up-regulated in pregnant patients. A ‘pregnancy-associated breast cancer signature’ was computed from the expression of the 28 genes. There was a negative relationship between the signature and the expression of ESR1 and PGR genes. This signature was significantly more correlated with the proliferation-associated AURKA gene in pregnant patients as compared to control (ρ = 0.73 vs ρ = 0.24, p = 0.001). Conclusions In this study, we were able to identify several genomic alterations associated with pregnancy that could help elucidate the impact of pregnancy on BC risk. Moreover, by combining CNAs with gene expression, we were able to identify genes that could be responsible for the poorer prognosis seen in pregnancy-associated breast cancer and could be potential drivers of this rare disease. Citation Format: Bastien Nguyen, David Venet, Françoise Rothé, Christine Desmedt, Samira Majjaj, Giancarlo Pruneri, David Brown, Fedro Peccatori, Hatem A. Azim, Christos Sotiriou. Interrogating the impact of pregnancy on breast cancer biology using DNA copy number profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1452. doi:10.1158/1538-7445.AM2017-1452