Abstract B63: Race and triple-negative breast cancer: Advances in noncoding RNA research together with a systems-biology-level analysis uncover key molecular differences

Abstract

Abstract Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is characterized by marked differences between Black/African-American (B/Aa) and White (Wh) women. Despite the great progress that has been achieved towards understanding the causes of race disparities in TNBC, there have been no system-level investigations of the problem from the standpoint of molecular oncology. We used the transcriptomic data from The Cancer Genome Atlas (TCGA) repository to study the normal breast and TNBC samples from Wh and B/Aa TNBC individuals that are contained in it. Specifically, our analysis integrated transcriptomic data from messenger RNAs (mRNAs), microRNAs (miRNAs), miRNA isoforms (isomiRs), and tRNA-derived fragments (tRFs). IsomiRs and tRFs are constitutive regulatory molecules that target genes and pathways through RNA interference (RNAi). In addition to RNAi, isomiRs and tRFs also have other modes of action that are not yet understood. IsomiRs and tRFs represent recent and very important advances in our understanding of post-transcriptional regulation in the cell. What makes them particularly relevant for this study is our having shown that the “footprint” of isomiRs and tRFs that are active in a cell depends strongly on a person's gender, race, and population origin, as well as on tissue type, tissue state, and disease type/subtype. We analyzed and compared TCGA samples from normal breast and TNBC and did so separately for B/Aa and Wh donors. As expected, we found many mRNAs to be differentially expressed. More importantly, when we compared B/Aa and Wh TNBC patients we found many mRNAs to be differentially wired. By this we mean that, even though the two groups of patients have many regulators and effectors in common, there are very extensive differences in the manner regulators interact with effectors in B/Aa and in Wh TNBC patients, respectively. Our accumulated evidence suggests strongly that this differential wiring is an important driver of the phenotypic differences that we observe between B/Aa and Wh TNBC patients. Our studies show that there is a multitude of regulatory molecules that are involved in this rewiring and the racial disparities in TNBC. Among isomiRs, we identified numerous isomiRs that arise from the mir-200c and mir-21 miRNA precursors, and from the oncogenic miR-17/92 and miR-183/96/182 clusters. Among tRFs, we identified many tRFs that arise from nuclear (e.g., Glycine, Leucine) and mitochondrial tRNAs (e.g., Valine, Proline). We showcase this race-specific rewiring with the help of MAPK and Wnt signaling, two metastasis-related pathways. The data-driven approaches that we employed in the analysis enabled us to carry out comprehensive studies of the transcriptomes of two states (normal and cancer) and two races (B/Aa and Wh). Our methodology allowed us to dissect the complex regulatory events that are mediated by isomiRs and tRFs. It also helped us unravel the significant roles that isomiRs and tRFs have in reshaping mRNA expression differentially in the two races. Collectively, our findings suggest that systems biology-level avenues may prove fruitful in the study of disparities in TNBC and in other cancers. Citation Format: Aristeidis G. Telonis, Isidore Rigoutsos. Race and triple-negative breast cancer: Advances in noncoding RNA research together with a systems-biology-level analysis uncover key molecular differences [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B63.