Abstract 2248: Dynamic changes in transposon expression and epigenetic regulators detected during early breast cancer transition to malignancy
Authors: Isaac D. Raplee, Alexei Evsikov, Caralina Marin de Evsikova
Journal: Cancer Research (2018)

Abstract Introduction: Breast cancer is the second leading cause of cancer-related deaths in women. In 2017, about 315,000 women were diagnosed with breast cancer, with approximately 63,000 new cases of ductal carcinoma in situ (DCIS), the earliest form of breast cancer. Little is known as to why some patients diagnosed with atypia and DCIS remain cancer-free while others progresses to invasive ductal carcinoma (IDC). Hypothesis: While mutagenic role of transposonable elements (TEs) in cancer is known, we test the novel role of long terminal repeat (LTR) TEs as potential drivers promoting cell de-differentiation during early stages of breast cancer. Objective: To identify molecular signatures driving cell fate decisions at atypia and DCIS to transformation, we investigated expression of TEs in atypia, DCIS and IDC. Methods: We created a TE Enrichment Set Analysis (TESA) to identify TEs in RNA sequencing datasets across four stages of breast cancer, normal atypia, DCIS, IDC (n= 8-23 samples per stage). Results: After quality control steps to remove outliers, TEs, compared to genes, exhibit substantially less variation in their expression because the first principal component accounted for over 80% expression variation compared to 20% in transcript expression variation (p&amp;lt;0.05). Eighty-eight TEs were detected as significant across stages by ANOVA (α=0.05, FDR 5%). The majority of differentially expressed TEs were LTRs (67%, p&amp;lt;0.05) with the remaining split into DNA TEs (18%), SINEs (11%) and unclassified (4%). Despite being the largest TE portion in the human genome, no statistically significant differences were detected in LINEs (p&amp;gt;0.10). Six general patterns of TE expression were identified using k-means clustering algorithm. In general, the majority of TEs were upregulated during atypia or DCIS stages or both stages. To identify potential molecular mechanisms of TE de-repression, which induce LTR expression during atypia and DCIS, we measured the correlation between specific LTRs, including HERV-H, HERV-K, LTR7Y, and expression of epigenetic regulators, TETs, DNMTs, and TRIM28/KAP1 across all four stages. As expected, normal tissue has positive and negative correlations between LTRs and epigenetic regulators, however, at atypia there was a loss of some negative correlations and at DCIS all negative correlations between LTRs and DNMTS were lost (p&amp;lt;0.0001). Unexpectedly, at IDC stage, the negative correlations re-emerged between LTRs and DNMTs (p&amp;lt;0.05). Together, these data imply the epigenetic remodeling occurs prior to malignancy, which associates, and may potentially drive, LTR expression. Conclusion: Our TESA data provides experimental support that early genomic changes are a mechanism underlying malignancy. Translational bioinformatics is a technique to identify prognostic molecules for impending invasive breast cancer from biopsies from pre-malignant stages. Citation Format: Isaac D. Raplee, Alexei Evsikov, Caralina Marin de Evsikova. Dynamic changes in transposon expression and epigenetic regulators detected during early breast cancer transition to malignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2248.