Abstract 4815: Differential expression profiling of long noncoding RNA establishes UCA1 as a hallmark of renal medullary carcinoma

Abstract

Abstract Renal medullary carcinoma (RMC) is a rare but highly lethal renal cell carcinoma (RCC) that predominantly afflicts young African Americans with sickle cell hemoglobinopathies. There are currently no approved targeted therapies for RMC and the median survival from diagnosis is 13 months despite best available treatments. New biomarkers and therapeutic targets are therefore urgently needed for this very aggressive disease. No studies to date have profiled the long noncoding RNA landscape of RMC. We performed RNA sequencing in untreated primary tumor samples obtained from 11 patients with RMC. The lncRNA expression profile of RMC was compared to that of adjacent normal kidney (n = 6 patients with RMC), upper tract urothelial carcinoma (UTUC), and closely related RCCs including collecting duct carcinoma (CDC), clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), and chromophobe renal cell carcinoma (chRCC). We performed principal component analyses as well as hierarchical clustering of the lncRNA expression levels using the Pearson correlation coefficient as the distance metric and the ward's linkage rule. The read counts of each lncRNA were fitted using a negative binomial model and a Wald test was used in DESeq2 to compare expression levels. The false discovery rate (FDR) was controlled using the Benjamini and Hochberg method. We found that the lncRNA signature of RMC is clearly distinct from that of ccRCC, pRCC, and chRCC, but substantially overlaps with CDC. Urothelial cancer associated 1 (UCA1) was the highest upregulated lncRNA (305-fold increase, FDR < 0.001) in RMC compared with adjacent normal kidney. This dramatic upregulation of UCA1 was similar to that seen in UTUC and not found in any of the other RCCs, including CDC. UCA1 is known to be associated with chemotherapy resistance and was previously considered to be highly specific for urothelial carcinoma. Our findings now suggest that UCA1 is also a hallmark of RMC. Future studies will focus on elucidating the functional consequences of UCA1 expression in RMC pathobiology. Citation Format: Pavlos Msaouel, Gabriel G. Malouf, Xiaoping Su, Hui Yao, Durga N. Tripathi, Jianjun Gao, Priya Rao, Jean-Philippe Bertocchio, Jose Karam, Christopher G. Wood, Cheryl L. Walker, Giannicola Genovese, Nizar M. Tannir. Differential expression profiling of long noncoding RNA establishes UCA1 as a hallmark of renal medullary carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4815.