Abstract P2-08-02: Chronic inflammation and the development of breast cancer

Background: Recently, The Breast Cancer Working Group of the International Cancer Genome Consortium examined the patterns of somatic mutations in the cancer genomes of 21 breast cancers. They generated 5 mutations signatures. While the mechanisms responsible for most of the signatures are unknown, the pattern of one of the signatures is similar to that observed when the APOBEC family of cytidine deaminases is active. Histologically normal tissue adjacent to a cancer provides a window into the early steps of oncogenesis. Comparison of this tissue to the cancer and to healthy, normal tissue frequently exposes a field effect/defect that changes progressively from healthy normal to adjacent normal to malignant. Comparing DNA expression in histologically normal tissue adjacent to cancer to that in normal, healthy breast tissue, we noted that the adjacent tissue is awash in inflammatory mediators. Inflammation causes genetic damage by the up-regulation of activation-induced cytidine deaminases and the production of reactive oxygen species. We hypothesize that the activation of the APOBEC family cytidine deaminases observed in a subset of the 21 breast cancers is a consequence of chronic inflammation. Methods: RNA-Seq data from adjacent normals was downloaded from the TCGA (The Cancer Genome Atlas) data portal. The epithelia from 20 frozen tissue cores from healthy premenopausal donors to the Susan G. Komen for the Cure® Tissue Bank at the IU Simon Cancer Center were microdissected and the RNA isolated. RNA-sequencing was carried out using the Life Technologies SOLiD Platform. RPKM gene expression values from TCGA and sequencing of the Komen normal tissues were merged, quantile normalized, and batch effect corrected. Normalization and differential gene expression was performed using Partek Genomics Suite. Results: The expression of APOBEC3C in adjacent normal is 3.4-times that in healthy normal (p = 4.94E-03). Additionally, reactive oxygen species in the form of nitric oxide are frequently generated by inflammatory cytokine production of Nitric Oxide Synthase. Nitric oxides can act by directly oxidizing DNA or by damaging DNA repair functions. Our preliminary data reveals that the expression of Nitric Oxide Synthase 3 in adjacent normal is 4-times that in healthy normal (p = 4.55E-03). Conclusions: In a review of inflammation-associated cancers published in Scientific American, Gary Stix remarks that “Genetic damage is the match that lights the fire of malignancy, and inflammation is the fuel that feeds the flames”. It is possible that inflammation is both the match and the fuel. The up-regulation of APOBEC in adjacent normal is likely the result of the induction of the NF-kB pathway in response to the diffusion of inflammatory mediators from the adjacent malignancy. Activated cytidine deaminases under normal, physiologic conditions contribute to the generation of antibody gene diversity in activated B lymphocytes by inducing somatic hypermutations and class switch recombination of immunoglobulin genes. However, when inappropriately expressed they produce mutagenesis. The differences in gene expression identified are some of the earliest changes in breast carcinogenesis and provide insight into the etiology of this disease and, potentially, its prevention. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-08-02.