Abstract MicroRNA (miRNA) isoforms (isomiRs), generated by alternative processing, RNA editing, and tailing/trimming, broaden regulation and can differ from canonical miRNAs in targets and function. Yet most cancer genomics workflows still collapse reads to canonical miRNAs or ignore non-canonical variants, obscuring isoform-specific regulatory networks. This gap is especially relevant in NSCLC, where heterogeneity and unmet needs in biomarkers and targets are high. Building on our pan-cancer data showing that isomiR-aware profiling improves clinicopathologic classification, we assumed that systematic isoform-level analysis would uncover NSCLC-specific biological signatures and vulnerabilities missed by traditional miRNA analyses. Data from TCGA LUAD and LUSC were processed with an isoform-aware pipeline. Differentially expressed isomiRs between tumors and matched normals were defined using |fold-change|>1.5 and FDR<0.05. Consensus targets were predicted across six algorithms, retaining interactions supported by ≥4 tools and downregulated in isomiR-high versus isomiR-low tumors. Isoform functions were compared across subtypes using Jaccard distances on pathway-level target matrices, hierarchical clustering, and pathway-frequency summaries across lung cancer-related pathways. We identified ∼1,300 deregulated isomiRs in LUAD and ∼1,100 in LUSC. Pathway-based clustering grouped isomiRs into functional clusters that separated LUAD and LUSC. Clusters enriched for hallmark oncogenic signaling networks (e.g., PI3K-AKT, MAPK, p53, VEGF) contained ∼14% shared isomiRs that converged on these pathways. miR-183-5p, which contributed the largest isoform repertoire, aligned with high cluster activity and PTEN/p53-AKT signaling. Oncogenic clusters were further shaped by miR-17-5p/miR-93-5p and context-dependent miR-130b-3p, whereas tumor-suppressive isomiRs (e.g., miR-128-3p) marked restraint of cell-cycle progression and invasion. Isoform-aware miRNA analysis uncovers NSCLC regulatory networks beyond traditional views. Integrating consensus targeting with cohort-level expression and pathway-based clustering enables functional identification of isomiRs and prioritization of isoform-target pairs, including subtype-specific and shared oncogenic networks, as potential biomarkers and therapeutic targets. These results are still limited by current challenges in isomiR quantification, context-specific target prediction, cohort variability, and the need for functional validation. Citation Format: Shaopeng Gu, Junhao Liu, Shaohong Feng, Rosario Distefano, Sebastiano Di Bella, Francesco Orilio, Rosario Brancaccio, Giulia Romano, Eswar Shankar, Mario Acunzo, Federica Calore, Christian Rolfo, Qin Ma, Giovanni Nigita. Isoform-aware miRNA network mapping in NSCLC via computational consensus targeting and functional clustering [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2055.

Tyrosine Kinase inhibitors (TKIs) are widely used as effective chemotherapeutic agents for treating patients with EGFR-mutated NSCLC. Unfortunately, after treatment, patients eventually develop resistance to TKI therapy. The most common resistance mechanism for the TKI Osimertinib is the overexpression of the MET Proto-Oncogene, Receptor Tyrosine Kinase (MET). We previously demonstrated that miR-411-5p A-to-I edited at position 5 (miR-411ed) can directly target MET in A549 and H1299 cells. MiR-411ed in combination with Osimertinib reduced cell proliferation in two TKI resistant EGFR-mutated cell lines: HCC827R and PC9R. MiR-411ed did not downregulate MET expression in HCC827R, suggesting an alternative mechanism for TKI response. In this study, we aim to identify the mechanism of miR-411ed TKI response using a multi-omics approach of RNAseq and protein mass spectrometry. In our cellular model, we identified miR-411ed affected genes independent of MET activity, resulting in 211 genes (RNAseq) and 36 proteins (proteomics). Pathway analysis identified an increase in interferon signaling for RNAseq and combined omics, and a decrease in ERK/MAPK signaling in proteomics. Using the IsoTar target prediction tool, we identified STAT3 as a key regulator and confirmed STAT3 protein downregulation upon transfection with miR-411ed. We further investigated the effect of miR-411ed in vivo, observing a reduction in tumor size with miR-411ed in combination with Osimertinib but not with miR-411ed or Osimertinib treatment alone, confirming the effectiveness of miR-411ed in TKI response.

MicroRNAs (miRNAs) are small non-coding RNAs that play essential roles in gene regulation, cellular function, and disease pathogenesis. Advances in single-cell RNA sequencing technologies have enabled the profiling of miRNAs at single-cell resolution, providing unprecedented insight into cell-specific regulatory networks and heterogeneity. This chapter presents an overview of miRNA biology, technical approaches for single-cell miRNA sequencing, and recent bioinformatics tools developed for data analysis. We discuss challenges in library preparation, such as adapter biases and low RNA input, and highlight integrative strategies for co-profiling miRNAs with other omics layers. Finally, we outline in the conclusion the potential of single-cell miRNA profiling to contribute to precision medicine and therapeutic development, including its possible use in biomarker discovery, monitoring tumor heterogeneity, and informing personalized treatment strategies. As the field progresses, continued innovation will be critical to overcoming existing barriers and fully harnessing the power of single-cell miRNA analyses.

Background: The sensitivity of pleural fluid cytology to diagnose malignant pleural effusion is around 60%. Patients with cytology-negative effusions often undergo repeated invasive procedures, increasing complications and causing diagnostic delays. To address this gap in clinical care, we sought to identify a pleural fluid extracellular microRNA for the diagnosis of malignant pleural effusion. Methods: Following RNA extraction from pleural fluid extracellular vesicles, differentially expressed microRNA were identified by Nanostring in a discovery cohort (n=24) of malignant and non-malignant effusions. The diagnostic performance of differentially expressed microRNA was assessed in multicenter independent validation cohorts of cytology-positive (n=52) and cytology-negative (n=38) malignant pleural effusion compared with various non-malignant effusion controls (total n=70) using reverse-transcriptase–quantitative polymerase-chain-reaction. Findings: Among the differentially expressed microRNAs identified in the discovery cohort, hsa-miR-141-3p was most differentially expressed comparing any MPE group versus non-malignant effusion. In cytology-positive malignant versus non-malignant effusion, hsa-miR-141-3p provided 86% diagnostic sensitivity and 97% specificity. In cytology-negative malignant versus non-malignant effusion, area under the receiver-operating-characteristic curve for hsa-miR-141-3p was 0·86 (95% confidence interval, 0·78 to 0·94). With a cytology-negative malignant effusion cohort prevalence of 46%, at a cutoff value of 22·5 ∆-cycle threshold, hsa-miR-141-3p had a positive predictive value of 77% and negative predictive value of 87% compared to a pleural fluid cytology negative predictive value of 54%. The association between hsa-miR-141-3p and malignant pleural effusion remained robust after adjustment for age, sex, race, smoking-status and transudative/exudative status. Interpretation: Pleural Fluid extracellular microRNA-141-3p differentiates between malignant pleural effusion and non-malignant effusion with high accuracy.

Over the past few decades, microRNAs (miRNAs) have gained significant attention for their role in regulating gene expression and their association with various diseases, including cancer. These small noncoding RNAs (sncRNAs) have been identified as crucial regulators of different biological functions. However, recent advancements in high-throughput sequencing technologies have revealed a more complex miRNAome, driven by phenomena such as RNA editing and isomiRs, which modify miRNA sequences. This increasing complexity has necessitated the development of new tools to analyze the miRNAome and better understand their biological roles. To address this challenge, isoTar was developed-a high-performance, web-based containerized application designed for miRNA consensus-targeting prediction and functional enrichment analyses. This chapter provides a comprehensive overview of isoTar ( https://ncrnaome.osumc.edu/isotar/ ), including benchmarks of its performance and a guide to its usage.

Extracellular vesicles (EVs) are produced by every organ, serving as vehicles for communication. By circulating throughout the body and targeting both neighboring and distant cells and organs, they can drive downstream signaling. EVs play a role as effectors of cell-to-cell communication in the tissue microenvironment and have demonstrated their importance in driving downstream biological processes, maintenance of homeostasis and response to stimuli. New methodologies supporting the study of EV-mediated long-distance communication have revealed a whole new unexplored function in maintaining homeostasis of the organism and serving as indicators of pathological conditions. In this review, we provide the most recent update on the role of EVs as mediators of intercellular and interorgan communication.

MicroRNA (miRNA) editing introduces a new layer of complexity in post-transcriptional gene regulation, with potential implications for miRNA biogenesis, target specificity, and function. However, the lack of a dedicated repository to comprehensively catalog miRNA editing events has hindered advances in the field. MiREDiBase addresses this gap by offering a meticulously curated database focused exclusively on validated, high-confidence putative miRNA editing events, with emphasis on A-to-I (adenosine-to-inosine) and C-to-U (cytidine-to-uridine) editing. This resource provides extensive annotations, including genomic locations, structural changes, and biological context, alongside tools for comparative analysis and predictive modeling of miRNA editing effects. MiREDiBase integrates data from experimental validation and high-throughput sequencing, delivering insights into the functional and pathological significance of miRNA editing across species. Unique features include a user-friendly interface for searching and comparing editing patterns, access to RESTful APIs for advanced data retrieval, and integration with external databases to enhance usability in epitranscriptomics research. By bridging the gap between RNA editing and miRNA research, MiREDiBase fosters innovative exploration of miRNA biology, advancing our understanding of its role in health and disease.

RATIONALE: Malignant pleural effusion (MPE) represents advanced malignant disease and based on cancer type, portends limited and varying prognosis. A combination of clinical and laboratory biomarkers such as the LENT score, are used to predict survival in MPE however, due to other unaccounted variables, the accuracy of the existing scoring systems is limited. With the advent of new therapeutics, the use of a tumor-specific marker of disease progression is critical. Previously, we isolated and characterized PF tumor-derived extracellular vesicles (EV) and their microRNA (miRNA/miR). We hypothesize that PF EV-miRNA may serve as a measurable prognostic biomarker in MPE. METHODS: Pleural fluid (PF) EV-miRNAs were profiled using NanoString technology in a discovery set (n= 24). The top 14 differentially expressed miRNA between MPE [caused by breast adenocarcinoma (BA) and lung adenocarcinoma (LA)] and non-MPE [due to decompensated heart or liver failure] were confirmed in an independent cohort (n=120) using RT-PCR. Patient survival data (time from MPE first noted on imaging to death), as well as ECOG performance status (at the time of PF collection), were used to assess disease progression and survival in the entire population (Univariable Cox model). The prognostic value of 14 target miRNA were evaluated individually within the entire MPE, as well as LA-MPE (n=40) and BA-MPE (n=24) groups, with non-MPE group as a control. Significant miRNA values were stratified based on 1, 3, 6, and >12 months survival. Survival curves were compared with LENT score. RESULTS: Analysis included 64 MPE patients and 56 non-MPE controls. Median survival was 3.5 months in LA-MPE, 12. 2 months in BA-MPE and 12.2 months in controls (Figure-1). PF extracellular miR-144-3p values were significantly associated with survival in MPE patients (log HR=7.40, p=0.0247) and when stratified by cancer type, remained significant in LA-MPE (log HR=6.00, p=0.049). No association was found between miR-144-3p and survival in the control group (Figure-1). LENT Scores were high (53% moderate, 37.5% high risk) and stratified patients by mortality in LA-MPE patients. High vs. intermediate vs. low miR-144-3p values significantly (p=0.0014) stratified patients by mortality in LA-MPE, with pronounced separation at 1, 3, and 6 months (Figure-1). CONCLUSION: Pleural fluid EV-miR-144-3p is associated with survival in LA-MPE and may be used as a prognostic biomarker. The role of PF EV-miRNA as a biomarker of disease activity and survival in MPE should be evaluated in larger cohorts.

Non-coding RNAs (ncRNAs) play crucial roles in gene expression regulation, translation, and disease development, including cancer. They are classified by size in short and long non-coding RNAs. This chapter focuses on the functional implications of adenosine-to-inosine (A-to-I) RNA editing in both short (e.g., miRNAs) and long ncRNAs. RNA editing dynamically alters the sequence and structure of primary transcripts, impacting ncRNA biogenesis and function. Notable findings include the role of miRNA editing in promoting glioblastoma invasiveness, characterizing RNA editing hotspots across cancers, and its implications in thyroid cancer and ischemia. This chapter also highlights bioinformatics resources and next-generation sequencing (NGS) technologies that enable comprehensive ncRNAome studies and genome-wide RNA editing detection. Dysregulation of RNA editing machinery has been linked to various human diseases, emphasizing the potential of RNA editing as a biomarker and therapeutic target. This overview integrates current knowledge and computational tools for studying ncRNA editing, providing insights into its biological significance and clinical applications.

Rationale: The diagnostic sensitivity of Pleural fluid (PF) cytology in malignant pleural effusions (MPE) diagnosis is about 50% on average and varies based on cancer histology. As a result, cytology negative (C-) effusions of unknown etiology undergo multiple and progressively more invasive procedures. In previous studies, we showed that extracellular vesicles (EVs) found in PF contain microRNAs, particularly miR-141-3p, that can distinguish (C+) MPE from non-malignant pleural effusion (non-MPE) with remarkable accuracy. To establish clinical utility of this approach, the next vital step is to determine whether miR-141-3p is effective in identifying (C-) MPEs. Methods: We profiled 798 miRNA using NanoString technology in a discovery set, and selected the top differentially expressed miRNA between MPE and non-MPE, followed by subsequent validation using real-time PCT (RT-PCR) in 64 (C+) MPEs [LA- and BA-MPE] and 56 non-MPE. MicroRNA-141-3p was superior to all miRNA/miRNA combinations in differentiating MPE vs non-MPE. Following this, EVs were isolated from cell-free PF of 29 (C-) MPE samples [lung adenocarcinoma (LA)-MPE=19, breast adenocarcinoma (BA)-MPE=10] where the diagnosis was made by subsequent invasive testing. After extraction, EVs were characterized by nanoparticle tracking analysis (NTA) and negative-stain transmission electron microscopy (NS-TEM) followed by total RNA extraction. The discriminatory role of miR-141-3p between (C-) MPE and non-MPE was examined, using real-time quantitative PCR (RT-PCR). Results: EVs were isolated from 29 (C-) MPE samples and underwent NTA and were further characterized by NS-TEM (Figure-1-A-C). In cell-free PF of (C-) MPE, we identified 4.86e+10 ± 1.9e+10 (mean and SD) EVs per ml (Figure-1D), compared to 4.94e+10 ± 2e+10 EVs per ml in (C+) MPE (n=12) and 2.6e+10 ± 1e+10 EVs per ml in non-MPE (n=12) with enrichment for EVs in the 70-200 nm size range. When compared with 56 non-MPE samples, miR-141-3p expression identified (C-) MPE with an AUC of > 0.98 (Brier score: 0.054) among all (C-) MPE groups vs non-MPE(Figure-1E-G, 1I); however, microRNA-141-3p expression did not discriminate LA-MPE from BA-MPE (AUC:0.50) (Figure-1H, 1I). Conclusion: Our findings show that pleural fluid is an abundant source of EVs in both C+ and C- MPEs and suggest that miR-141-3p can differentiate between (C-) MPE and non-MPE with remarkable accuracy. These promising results should be confirmed within larger cohorts and MPEs of different tissue of origin.

The 5' cap, catalyzed by RNA guanylyltransferase and 5'-phosphatase (RNGTT), is a vital mRNA modification for the functionality of mRNAs. mRNA capping occurs in the nucleus for the maturation of the functional mRNA and in the cytoplasm for fine-tuning gene expression. Given the fundamental importance of RNGTT in mRNA maturation and expression there is a need to further investigate the regulation of RNGTT. N6-methyladenosine (m(6)A) is one of the most abundant RNA modifications involved in the regulation of protein translation, mRNA stability, splicing, and export. We sought to investigate whether m(6)A could regulate the expression and activity of RNGTT. In this short report, we demonstrated that the 3'UTR of RNGTT mRNA is methylated with m(6)a by the m(6)A writer methyltransferase 3 (METTL3). Knockdown of METTL3 resulted in reduced protein expression of RNGTT. Sequencing of capped mRNAs identified an underrepresentation of ribosomal protein mRNA overlapping with 5' terminal oligopyrimidine (TOP) mRNAs, and genes are dysregulated when cytoplasmic capping is inhibited. Pathway analysis identified disruptions in the mTOR and p70S6K pathways. A reduction in RPS6 mRNA capping, protein expression, and phosphorylation was detected with METTL3 knockdown

Therapy of melanoma has improved dramatically over the last years thanks to the development of targeted therapies (MAPKi) and immunotherapies. However, drug resistance continues to limit the efficacy of these therapies. Our research group has provided robust evidence as to the involvement of a set of microRNAs in the development of resistance to target therapy in BRAF-mutated melanomas. Among them, a pivotal role is played by the oncosuppressor miR-579-3p. Here we show that miR-579-3p and the microphthalmia-associated transcription factor (MITF) influence reciprocally their expression through positive feedback regulatory loops. In particular we show that miR-579-3p is specifically deregulated in BRAF-mutant melanomas and that its expression levels mirror those of MITF. Luciferase and ChIP studies show that MITF is a positive regulator of miR-579-3p, which is located in the intron 11 of the human gene ZFR (Zink-finger recombinase) and is co-transcribed with its host gene. Moreover, miR-579-3p, by targeting BRAF, is able to stabilize MITF protein thus inducing its own transcription. From biological points of view, early exposure to MAPKi or, alternatively miR-579-3p transfection, induce block of proliferation and trigger senescence programs in BRAF-mutant melanoma cells. Finally, the long-term development of resistance to MAPKi is able to select cells characterized by the loss of both miR-579-3p and MITF and the same down-regulation is also present in patients relapsing after treatments. Altogether these findings suggest that miR-579-3p/MITF interplay potentially governs the balance between proliferation, senescence and resistance to therapies in BRAF-mutant melanomas.

IntroductionSmall cell lung cancer (SCLC) is characterized by poor prognosis and challenging diagnosis. Screening in high-risk smokers results in a reduction in lung cancer mortality, however, screening efforts are primarily focused on non-small cell lung cancer (NSCLC). SCLC diagnosis and surveillance remain significant challenges. The aberrant expression of circulating microRNAs (miRNAs/miRs) is reported in many tumors and can provide insights into the pathogenesis of tumor development and progression. Here, we conducted a comprehensive assessment of circulating miRNAs in SCLC with a goal of developing a miRNA-based classifier to assist in SCLC diagnoses.MethodsWe profiled deregulated circulating cell-free miRNAs in the plasma of SCLC patients. We tested selected miRNAs on a training cohort and created a classifier by integrating miRNA expression and patients’ clinical data. Finally, we applied the classifier on a validation dataset.ResultsWe determined that miR-375-3p can discriminate between SCLC and NSCLC patients, and between SCLC and Squamous Cell Carcinoma patients. Moreover, we found that a model comprising miR-375-3p, miR-320b, and miR-144-3p can be integrated with race and age to distinguish metastatic SCLC from a control group.DiscussionThis study proposes a miRNA-based biomarker classifier for SCLC that considers clinical demographics with specific cut offs to inform SCLC diagnosis.

Non-small cell lung cancer (NSCLC) patients carrying an epidermal growth factor receptor (EGFR) mutation have an initial favorable clinical response to the tyrosine kinase inhibitors (TKIs). Unfortunately, rapid resistance occurs mainly because of genetic alterations, including amplification of the hepatocyte growth factor receptor (MET) and its abnormal activity. The RNA post-transcriptional modifications that contribute to aberrant expression of MET in cancer are largely under-investigated and among them is the adenosine-to-inosine (A-to-I) RNA editing of microRNAs. A reduction of A-to-I editing in position 5 of miR-411-5p has been identified in several cancers, including NSCLC. In this study, thanks to cancer-associated gene expression analysis, we assessed the effect of the edited miR-411-5p on NSCLC cell lines. We found that edited miR-411-5p directly targets MET and negatively affects the mitogen-activated protein kinases (MAPKs) pathway. Considering the predominant role of the MAPKs pathway on TKIs resistance, we generated NSCLC EGFR mutated cell lines resistant to TK inhibitors and evaluated the effect of edited miR-411-5p overexpression. We found that the edited miR-411-5p reduces proliferation and induces apoptosis, promoting EGFR TKIs response in NSCLC-resistant cells.

Supplementary Table from Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer

miRNAs are some of the most well-characterized regulators of gene expression. Integral to several physiological processes, their aberrant expression often drives the pathogenesis of both benign and malignant diseases. Similarly, DNA methylation represents an epigenetic modification influencing transcription and playing a critical role in silencing numerous genes. The silencing of tumor suppressor genes through DNA methylation has been reported in many types of cancer and is associated with tumor development and progression. A growing body of literature has described the crosstalk between DNA methylation and miRNAs as an additional layer in the regulation of gene expression. Methylation in miRNA promoter regions inhibits its transcription, while miRNAs can target transcripts and subsequently regulate the proteins responsible for DNA methylation. Such relationships between miRNA and DNA methylation serve an important regulatory role in several tumor types and highlight a novel avenue for potential therapeutic targets. In this review, we discuss the crosstalk between DNA methylation and miRNA expression in the pathogenesis of cancer and describe how miRNAs influence DNA methylation and, conversely, how methylation impacts the expression of miRNAs. Finally, we address how these epigenetic modifications may be leveraged as biomarkers in cancer.

Lung and breast cancer are the two most common causes of malignant pleural effusion (MPE). MPE diagnosis plays a crucial role in determining staging and therapeutic interventions in these cancers. However, our understanding of the pathogenesis and progression of MPE at the molecular level is limited. Extracellular Vesicles (EVs) and their contents, including microRNAs (miRNAs), can be isolated from all bodily fluids, including pleural fluid. This study aims to compare EV-miRNA patterns of expression in MPE caused by breast (BA-MPE) and lung (LA-MPE) adenocarcinomas compared to the control group of heart-failure-induced effusions (HF-PE). We conducted an analysis of 24 pleural fluid samples (8 LA-MPE, 8 BA-MPE, and 8 HF-PE). Using NanoString technology, we profiled miRNAs within EVs isolated from 12 cases. Bioinformatic analysis demonstrated differential expression of miR-1246 in the MPE group vs. HF-PE group and miR-150-5p and miR-1246 in the BA-MPE vs. LA-MPE group, respectively. This difference was demonstrated and validated in an independent cohort using real-time PCR (RT-PCR). miRNA-1246 demonstrated 4-fold increased expression (OR: 3.87, 95% CI: 0.43, 35) in the MPE vs. HF-PE group, resulting in an area under the curve of 0.80 (95% CI: 0.60, 0.99). The highest accuracy for differentiating MPE vs. HF-PE was seen with a combination of miRNAs compared to each miRNA alone. Consistent with prior studies, this study demonstrates dysregulation of specific EV-based miRNAs in breast and lung cancer; pleural fluid provides direct access for the analysis of these EV-miRNAs as biomarkers and potential targets and may provide insight into the underlying pathogenesis of tumor progression. These findings should be explored in large prospective studies.

The epitranscriptome encompasses all post-transcriptional modifications that occur on RNAs. These modifications can alter the function and regulation of their RNA targets, which, if dysregulated, result in various diseases and cancers. As with other RNAs, miRNAs are highly modified by epitranscriptomic modifications such as m6A methylation, 2′-O-methylation, m5C methylation, m7G methylation, polyuridine, and A-to-I editing. miRNAs are a class of small non-coding RNAs that regulates gene expression at the post-transcriptional level. miRNAs have gathered high clinical interest due to their role in disease, development, and cancer progression. Epitranscriptomic modifications alter the targeting, regulation, and biogenesis of miRNAs, increasing the complexity of miRNA regulation. In addition, emerging studies have revealed crosstalk between these modifications. In this review, we will summarize the epitranscriptomic modifications—focusing on those relevant to miRNAs—examine the recent crosstalk between these modifications, and give a perspective on how this crosstalk expands the complexity of miRNA biology.

Despite the development of targeted therapeutics, immunotherapy, and strategies for early detection, lung cancer carries a high mortality. Further, significant racial disparities in outcomes exist for which the molecular drivers have yet to be fully elucidated. The growing field of Epitranscriptomics has introduced a new layer of complexity to the molecular pathogenesis of cancer. RNA modifications can occur in coding and non-coding RNAs, such as miRNAs, possibly altering their gene regulatory function. The potential role for such modifications as clinically informative biomarkers remains largely unknown. Here, we concurrently profiled canonical miRNAs, shifted isomiRs (templated and non-templated), and miRNAs with single-point modification events (RNA and DNA) in White American (W) and Black or African American (B/AA) lung adenocarcinoma (LUAD) patients. We found that while most deregulated miRNA isoforms were similar in W and B/AA LUAD tissues compared to normal adjacent tissues, there was a subgroup of isoforms with deregulation according to race. We specifically investigated an edited miRNA, miR-151a-3p with an A-to-I editing event at position 3, to determine how its altered expression may be associated with activation of divergent biological pathways between W and B/AA LUAD patients. Finally, we identified distinct race-specific miRNA isoforms that correlated with prognosis for both Ws and B/AAs. Our results suggested that concurrently profiling canonical and non-canonical miRNAs may have potential as a strategy for identifying additional distinct biological pathways and biomarkers in lung cancer.