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Non-Coding RNA Profiles as a Determinant of Prognosis in Non-Muscle-Invasive Micropapillary Bladder Cancer - Expert Commentary

Micropapillary bladder cancer is a rare and aggressive variant of bladder cancer. Extensive research has focused on molecular subtyping of bladder cancer as a predictor of prognosis and response to treatment. Luminal tumors have been associated with better patient prognosis, although aggressive micropapillary tumors are often classified as luminal tumors. Most molecular studies on bladder cancer tissue have focused on mRNA sequencing. However, long non-coding RNAs (lncRNAs) are also known to be altered in bladder cancer molecular subtypes. A recent study by de Jong et al. examined the role of lncRNA expression profiles could identify high-grade T1 micropapillary bladder cancers.


To do so, the investigators extracted relevant data for 84 patients with high-grade T1 bladder cancer from a previously published retrospective cohort enriched for micropapillary histology. Most samples were classified as luminal tumors, and differential gene expression analysis showed that luminal markers (UPK1B, UPK3A, KRT20) were upregulated in primary micropapillary samples relative to urothelial tumors. Various lncRNAs previously associated with bladder cancer were significantly downregulated in micropapillary samples (UCA1, LINC00152, MALAT1). The investigators developed and applied a lncRNA-based single-sample genomic classifier to identify samples with activated fibroblast growth factor receptor 3 (FGFR+) status associated with less aggressive tumors. None of the micropapillary tumors were classified as FGFR3-positive. On the other hand, micropapillary tumors showed higher epithelial-to-mesenchymal (EMT) activity and lower sonic hedgehog (SHH) and p53 signature scores. 

Upon unsupervised clustering of 160 highly variant lncRNAs, three distinct clusters emerged. The lncRNA cluster 1 (LC1) associated with a worse prognosis was enriched for primary micropapillary histology and the Luminal Unstable (LumU) molecular subtype. Patients with tumors in this cluster showed significantly lower progression-free survival and overall survival rates compared to other clusters. To highlight the clinical relevance of the findings, de Jong et al. also established a single-sample signature that could identify aggressive bladder cancer and micropapillary biology. The samples classified as micropapillary tumors showed similar gene expression patterns and molecular signatures as those reported above and worse survival.

Molecular subtyping and in-depth classifications of bladder cancer can guide the prediction of clinical outcomes and treatment response. Including lncRNA profiles can therefore provide crucial additional information. Further prospective studies will be needed to validate the findings reported in de Jong et al.’s study. Studying histological variants, including the micropapillary variant, is often challenging due to their relative rarity.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

References:

  1. de Jong JJ, Valderrama BP, Perera J, et al. Non-muscle-invasive micropapillary bladder cancer has a distinct lncRNA profile associated with unfavorable prognosis [published online ahead of print, 2022 Apr 21]. Br J Cancer. 2022;10.1038/s41416-022-01799-2. doi:10.1038/s41416-022-01799-2

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