Abstract PR04: The molecular biology of nuclear and mitochondrial regulatory noncoding RNAs differs between white and African American patients with triple-negative breast cancer
Authors: Telonis Aristeidis G. , Loher Phillipe , Jing Yi , Londin Eric , Rigoutsos Isidore 
Published: May 2016

Noncoding RNAs (ncRNAs) are molecules that do not code for proteins but regulate cell physiology via multiple mechanisms. Through studies of hundreds of human datasets from healthy individuals and patients we found for two categories of ncRNAs that their composition and abundances depend on a person's gender, population, race, and several other variables. These two categories are: a) isoforms of microRNAs (miRNAs), also known as isomiRs; and, b) fragments derived from transfer RNAs (tRNAs), also known as tRNA fragments or tRFs.

Traditionally, a miRNA genomic locus was thought to give rise to a single mature miRNA (archetype). The archetype's sequence was recorded in public databases and used to design reagents and experiments. Advances in sequencing technology have revealed that miRNA loci simultaneously give rise to multiple isomiRs, i.e. isoforms of the archetype miRNAs, with distinct endpoints and abundances. Importantly, isoforms are loaded on the RNA-induced silencing complex (RISC) thereby entering the RNA interference (RNAi) pathway where they guide sequence-based RISC interactions with specifically targeted messenger RNAs (mRNAs) and ncRNAs, thusly controlling the abundance of those transcripts. Moreover, miRNAs have been linked to a multitude of cellular processes in health and disease.

Analogously, the genomic loci harboring tRNAs were thought to give rise to only the mature tRNA sequence, the latter being an integral part of the translation of mRNAs into amino acid sequences. As with isomiRs, modern sequencing technology revealed the existence of tRNA fragments that co-exist with the corresponding full-length mature tRNAs. Fast accumulating evidence has already linked tRFs to cell growth, cell proliferation, response to DNA damage, translation initiation, response to stress, etc. Some tRFs have also been found on RISC and to participate in RNAi, similarly to isomiRs.

We investigated isomiRs and tRFs in human samples, in health and disease. Specifically, we used public transcriptomic datasets from the 1,000 Genomes Project and from The Cancer Genome Atlas (TCGA) repository at the National Institutes of Health. By analyzing samples from nearly five hundred healthy individuals we found that both the isomiR profiles and the tRF profiles depend on a person's gender, population, race, tissue and tissue state. In the case of tRNA fragments, we found that they derive from nuclear and from mitochondrial tRNAs.

By focusing on data from cancer patients we found that the dependencies we uncovered extend to the disease context as well. In particular, our analysis of samples from White and African-American triple negative breast cancer (TNBC) patients showed that there exist extensive and significant differences in the isomiR and tRF profiles between the two races. More specifically, we identified many isomiRs and tRFs that are differentially abundant in TNBC samples from White patients vs. TNBC samples from African-American patients. We also found that analogous isomiR and tRF differences distinguish the normal breast samples of White and African American subjects. When we integrated the isomiR information with mRNA expression values from the corresponding TCGA TNBC samples we found that the molecular biology differences in the isomiR and tRF profiles were indeed reflected in the abundance of protein coding genes, a result that could serve as a starting point for deeper research activities towards explaining health disparities in this breast cancer subtype.

Our studies suggest that miRNA isoforms and tRNA fragments are active novel members of the molecular biology of TNBC. Future studies of this disease will need to also consider these molecules given that they represent a component of the cell's regulatory layer that depends on the patient's race.

This abstract is also presented as Poster C62.

Citation Format: Aristeidis G. Telonis, Phillipe Loher, Yi Jing, Eric Londin, Isidore Rigoutsos. The molecular biology of nuclear and mitochondrial regulatory noncoding RNAs differs between white and African American patients with triple-negative breast cancer. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr PR04.