Abstract PO-127: The short non-coding RNAs known as “ribosomal RNA-derived fragments” (rRFs) are linked to race disparities in TNBC
Authors: Cherlin Tess , Jing Yi , Rigoutsos Isidore 
Published: December 2020

Triple negative breast cancer (TNBC) cases contribute to 10-20% of all breast cancer cases in the United States. After accounting for modifiable factors such as socioeconomic disparities, TNBC cases continue to be more severe, and more metastatic in Black/African American (B/Aa) women compared to White (Wh) women. To date, no mutations in cancer-linked genes have been found that could explain these differences. This suggests the possibility that other factors contribute to the observed disparities. We have been studying two types of small non-coding RNAs (sncRNAs), which regulate gene expression, the isoforms of microRNAs (miRNAs) known as isomiRs, and the fragments of transfer RNA (tRNA) known as tRFs. We showed that the expression profiles of isomiRs and tRFs depend on tissue, and a person’s sex and population of origin. Importantly, we showed that in TNBC isomiRs and tRFs have different expression profiles and regulate different pathways in B/Aa and Wh patients, respectively. We recently characterized a third type of sncRNA, the ribosomal RNA-derived fragments (rRFs). We found that rRF expression also depends on tissue, and a person’s sex and population of origin, like isomiRs, and tRFs. Preliminary evidence from RNA Immunoprecipitations in TNBC model cell lines suggest that rRFs are bound to AGO2, which in turn links rRFs to RNA interference (RNAi). To determine whether rRFs are also linked to the molecular biology of TNBC disparities, we analyzed the expression of rRFs and messenger RNAs (mRNAs) expression in TNBC samples from B/Aa and Wh patients. We used gene co- expression analysis to study publicly available data from B/Aa and Wh TNBC patients. We identified 3,398 statistically significant rRFs and 10,266 statistically significant mRNAs. Of these, 1,681 rRFs are significantly correlated with 1,014 mRNAs (adjusted p-value ⇐ 0.05) in various combinations. 1,328 rRF-mRNA correlations are unique to B/Aa patients. 3,474 rRF-mRNA correlations are unique to Wh patients. Only 34 rRF- mRNA correlations are common to both groups of patients, suggesting that the rRF- mRNA correlations are population-dependent. Notably, the rRF-mRNA correlations that are unique to the B/Aa TNBC patients involve mRNAs that promote angiogenesis, metastasis, and cell proliferation, and suppress apoptosis. On the other hand, the rRF-mRNA correlations that are unique to the Wh TNBC patients involve mRNAs that promote cell proliferation. We investigated these findings further by transfecting select rRFs into TNBC cell lines from B/Aa (MDA-MB-468) and Wh (MDA-MB-231) donors. We found that transfecting these rRFs generated different changes in the expression of both mRNAs and rRNAs in the two cell lines. rRFs are emerging as a third category of sncRNAs that modulate regulatory differences between B/Aa and Wh patients in TNBC. Future work will determine their biogenesis, shed more light on their functions, and elucidate the full spectrum of events by which they contribute to health disparities in TNBC.

Citation Format: Tess Cherlin, Yi Jing, Isidore Rigoutsos. The short non-coding RNAs known as “ribosomal RNA-derived fragments” (rRFs) are linked to race disparities in TNBC [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-127.