Abstract
Abstract Background: MicroRNAs (miRNAs) are small noncoding RNAs that bind mRNA and inhibit translation or encourage degradation. MiRNAs play a significant regulatory role, with approximately 60% of protein-coding genes harboring miRNA binding sites. MiRNA dysregulation is associated with tumor onset, growth, and metastasis. These important regulatory RNAs have been studied as potential cancer biomarkers, yet the widespread adoption of any miRNA signature has been hindered by the variable nature of miRNA targeting, which is highly context specific. Total tumor cell mRNA content, or TmS, has been shown to have potential as a pan-cancer prognostic indicator. Here we expand the TmS framework using deconvolved miRNA expression to calculate TmiS, an estimate of total tumor-cell miRNA content and investigate the utility of TmiS as a prognostic marker in prostate cancer. Methods: Whole exome sequencing and miRNA sequencing, along with clinical annotations were downloaded for prostate cancer patient samples from The Cancer Genome Atlas (TCGA). Sample purity and ploidy were estimated from exomes using ASACT and ABSOLUTE. Tumor miRNA proportion was estimated using our previously developed miRNA deconvolution method DeMixMir, and TmiS, the total miRNA content per haploid genome per tumor cell, was calculated for each sample. Patients were separated by Gleason category and were binarized into High-TmiS and Low-TmiS within samples with Gleason 7 and Gleason 8+ scores separately. Results: We find Low-TmiS patients to have significantly better prognosis in both Gleason 7 (P = 0.04) and Gleason 8+ (P = 0.01) prostate cancer. We confirm that TmiS is indeed an aggregate measure of total miRNA levels, with no strong correlations observed with any one miRNA. We identify differentially expressed miRNAs and mRNAs between high and low TmiS, and find distinct enriched pathways between Gleason 7 and Gleason 8+ samples, and that several of the differentially expressed miRNAs are well-characterized cancer-related transcripts. Conclusions: In spite of their important regulatory function, the variable and context specific nature of miRNA targeting has been a barrier to their implementation as a robust biomarker. We find TmiS to be a measure of total miRNA dysregulation, and that patients with high total miRNA content show poorer survival within prostate samples graded at Gleason 7 (as well as Gleason 8+), which has been a challenging group for further risk classification. In summary, while the consequences of miRNA dysregulation are subtype specific, we find that by measuring total tumor cell miRNA, TmiS has potential as a robust prognostic indicator independent cellular context. Citation Format: Matthew Montierth, Kinga Németh, George A. Calin, Wenyi Wang. TmiS: A prognostic indicator for prostate cancer survival based on total tumor cell miRNA levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2993.
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