Short noncoding RNAs (ncRNAs) have been attracting increasing interest as regulators of messenger RNA (mRNA) abundance. Such regulatory molecules can have influence the abundance of mRNAs both positively and negatively. Two important categories of short ncRNAs are microRNAs (miRNAs) and their isoforms (isomiRs), and the tRNA-derived fragments (tRFs). We previously showed that their “wiring” with mRNA abundance strongly depends on the race/ethnicity in triple-negative breast cancer. Here, we focused on two cancers, bladder urothelial carcinoma (BLCA) and stomach adenocarcinoma (STAD). Men and women have been known to exhibit different incidence rates of BLCA, as well as differences in invasion, and overall aggressiveness. Analogous observations hold true when comparing White and Asian individuals in the case of STAD. We mined a total of 615 primary tumors, 337 from STAD and 278 from BLCA patients. After stringent abundance filtering, we identified 1,478 distinct isomiRs and 355 distinct tRFs. We found that the abundance profiles of these molecules exhibited strong tissue dependencies. We constructed gene co-expression networks for the healthy and disease states. Mining the correlations of isomiRs/tRFs with mRNAs, we found that core cancer pathways are wired with small ncRNAs. We carried out a large-scale computational analysis of the correlation patterns to dissect the dependencies on race/ethnicity and sex in STAD and BLCA, respectively. We found that core pathways are differentially wired in each case. For example, in BLCA, cell cycle genes are linked with several tRFs in one sex but not in the other. While the contribution of isomiRs in sex disparities in BLCA is limited, we find that isomiRs exhibit strong sex-independent associations with immune system responses and extracellular matrix and cell adhesion. In the case of STAD, we observed several instances of differential-by-race/ethnicity correlations of tRFs with genes involved in cell signaling, like ITPA and PICK1 and numerous cell adhesion genes differentially wired with isomiRs. Our data provide a detailed perspective of the structure and hubs of the gene expression networks in BLCA and STAD as well as their sex- and race/ethnicity-specific components. The identification and discovery of context-specific potential regulators have considerable ramifications for precision medicine and can be leveraged to facilitate the design of better-targeted treatments that are tuned to the patient's sex and race.

Citation Format: Aristeidis G. Telonis, Isidore Rigoutsos. The wiring between genes and short noncoding RNAs in cancer depends on race/ethnicity and sex [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C010.

©2020 American Association for Cancer Research.
2020
American Association for Cancer Research.