Abstract
We define transcriptomic heterogeneity (TH) as the phenomenon wherein “the same exact segment of DNA produces different RNA products either in different tissues of the same individual, or in the same tissue of individuals who differ in one or more variables such as sex, population origin, race, age, etc.” In TH, the disease state is associated with differences in the RNA molecules that are produced from a given segment of DNA. This differs from genomic heterogeneity wherein one associates a disease state with variations and polymorphisms in the DNA template itself. We have shown that TH is relevant to the study of race disparities in breast and prostate cancers, and implicated two classes of non-coding RNAs (ncRNAs): microRNAs and transfer RNAs. Next, we describe our findings separately for each class.
MicroRNAs (miRNAs) are a well-known class of powerful regulators that control the abundance of messenger RNAs (mRNAs), and, thus, of proteins, in animals and plants. MiRNA studies long assumed that each arm of the miRNA precursor produced at most one consequential mature miRNA. Rapidly emerging data have now revealed a complex picture whereby a given miRNA precursor arm simultaneously produces a cloud of isoforms, the isomiRs, with 5´ and 3´ endpoints that differ slightly from one another's.
Emerging findings suggest that isomiRs represent a fundamental paradigm shift in how to study the roles of miRNAs in cancer and force us to reconsider the conventional view of “one-miRNA-precursor-arm-one-product.” Firstly, isomiRs are known to enter the RNA interference (RNAi) pathway and thus have functional roles in regulating transcript and protein abundance. Secondly, we showed that in healthy individuals and cancer patients, the identities and abundances of the isomiRs produced by a miRNA genomic locus depend on a person's race, sex, and population origin and also on tissue type, disease subtype, and possibly other variables. Thirdly, using BT-20 and MDA-MB-468, two cell lines modeling triple negative breast cancer (TNBC) in White (Wh) and Black or African American (B/Aa) patients respectively, we demonstrated that distinct isomiRs from the same miRNA locus can target largely non-overlapping groups of mRNAs. Fourthly, using the same two cell lines (BT-20 and MDA-MB-468) we showed that the impact on proliferation by a given isomiR differs by race.
Transfer RNAs (tRNAs) were discovered sixty years ago. tRNAs are present in all three kingdoms of life. The conventional understanding had been that the genomic loci encoding tRNAs produce a precursor transcript which is processed to give rise to the mature tRNA used in codon translation. As was the case with miRNAs, the analysis of deep sequencing data revealed that tRNA fragments, known as tRFs, are produced from the full-length premature or mature tRNAs.
We carried out parallel investigations of the profiles of tRFs across hundreds of healthy individuals and cancer patients and were able to generate several key results. Firstly, we showed that tRFs are produced constitutively in healthy people and in cancer patients. Secondly, we showed that the identities and abundances of the tRFs produced by a tRNA genomic locus depend on a person's race, sex, and population origin and also on tissue type, disease subtype, and possibly other variables. Thirdly, we showed that tRFs from the same tRNA alter the expression of largely non-overlapping groups of mRNAs. Fourthly, we showed that the impact on proliferation by a given tRF differs by race.
Our findings show that isomiRs and tRFs are newly discovered important regulators whose roles depend on a patient's race. These currently uncharacterized molecules need to be taken into account in studies of race-based cancer disparities.
Citation Format: Isidore Rigoutsos, Aristeidis G. Telonis, Phillipe Loher, Rogan Magee, Yi Jing, Eric Londin. Transcriptomic Heterogeneity of microRNA Isoforms and tRNA Fragments contributes to Race-based Differences in Breast and Prostate Cancers. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B43.
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