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Abnormal histone modifications (HMs) can promote the occurrence of breast cancer. To elucidate the relationship between HMs and gene expression, we analyzed HM binding patterns and calculated their signal changes between breast tumor cells and normal cells. On this basis, the influences of HM signal changes on the expression changes of breast cancer-related genes were estimated by three different methods. The results showed that H3K79me2 and H3K36me3 may contribute more to gene expression changes. Subsequently, 2109 genes with differential H3K79me2 or H3K36me3 levels during cancerogenesis were identified by the Shannon entropy and submitted to perform functional enrichment analyses. Enrichment analyses displayed that these genes were involved in pathways in cancer, human papillomavirus infection, and viral carcinogenesis. Univariate Cox, LASSO, and multivariate Cox regression analyses were then adopted, and nine potential breast cancer-related driver genes were extracted from the genes with differential H3K79me2/H3K36me3 levels in the TCGA cohort. To facilitate the application, the expression levels of nine driver genes were transformed into a risk score model, and its robustness was tested via time-dependent receiver operating characteristic curves in the TCGA dataset and an independent GEO dataset. At last, the distribution levels of H3K79me2 and H3K36me3 in the nine driver genes were reanalyzed in the two cell lines and the regions with significant signal changes were located.
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