Abstract
Simple SummaryPost-transcriptional modification events in miRNA molecules have revealed a more complex layer to cancer biology. Such modifications have created a novel path to developing and testing potential cancer biomarkers. Here, we concurrently profiled canonical and non-canonical miRNA molecules in White American (W) and Black or African American (B/AA) lung adenocarcinoma (LUAD) patients from The Cancer Genome Atlas (TCGA) cohort. We identified distinct potential post-transcriptional modifications in lung cancer tissues from W versus B/AA patients. Our results suggested the relevance of miRNA isoforms as potential biomarkers in lung cancer.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.
Highlights
In the United States, lung cancer remains the leading cause of cancer death in males and females
single nucleotide variant (SNV) occurring in miRNA sequences were further annotated with A-to-I RNA editing sites (MiREDiBase database [35]), somatic mutations (COSMIC database [36], and The Cancer Genome Atlas (TCGA) and TARGET cohorts), and known Single Nucleotide Polymorphisms (SNPs) [37]
We identified a total of 5582 expressed miRNA isoforms in the LUADTCGA cohort (3785 in W normal tissues, 3832 in W tumor tissues, 4137 in Black or African American (B/AA) normal tissues, and 3881 in B/AA tumor tissues)
Summary
In the United States, lung cancer remains the leading cause of cancer death in males and females. Lung cancer disproportionally affects Black or African American (B/AA) males, exemplified by higher incidence and mortality rates than in other reported racial and ethnic groups [2,3]. Under the 2013 USPSTF recommendations, individuals aged 55–80 years old with a minimum 30-pack/year smoking history are eligible for LCS (REF). In 2021, the USPSTF broadened its criteria for LCS to individuals aged 50–80 years old with a minimum of 20-pack/year smoking history [12]. Smoking is implicated with a higher risk of developing lung cancer, it is clear that other factors contribute to the observed racial disparities in lung cancer incidence and mortality [6,8,11]
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