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Abstract
Liquid biopsy has emerged as a novel and highly promising method for the non-invasive analysis of tumor-specific genetic alterations. In clinical practice, the most widely adopted application involves screening circulating tumor DNA (ctDNA) for mutations associated with resistance to targeted therapy. For lung adenocarcinoma patients, a positive ctDNA test result often warrants a change in therapeutic agent. Liquid biopsy is being explored for other critical applications, including early cancer detection and disease monitoring. However, these efforts face significant technical challenges. A key limitation is that many tumors, particularly in early stages, release insufficient amounts of DNA into the bloodstream for reliable molecular analysis. Circulating tumor RNA (ctRNA) represents a less conventional but theoretically compelling alternative. This suggests that RNA-based diagnostics could address the central limitation of ctDNA analysis: the scarcity of tumor-derived DNA in sampled blood. Unlike nuclear DNA, RNA transcripts are continuously produced by tumor cells in high copy numbers, potentially offering greater abundance in biological fluids. Non-invasive RNA diagnostics may replicate the capabilities of DNA-based liquid biopsy. For instance, RNA markers enable direct or indirect evaluation of therapeutic targets status for targeted therapy. In certain scenarios, such as detecting chimeric gene transcripts from clinically significant translocations, ctRNA analysis clearly outperforms ctDNA-based methods. The tumor transcriptome encompasses a large number of functional and structural categories, different in their chemical stability, representation in blood and across biological fluids, including mRNA, microRNA, long non-coding RNA, and circular RNA. Tumor-derived RNA circulates in plasma incorporated into nucleoprotein complexes, extracellular vesicles, platelets, or circulating tumor cells. This biological diversity has led to a proliferation of RNA-based liquid biopsy approaches, complicating standardization and clinical implementation. To date, only a limited number of pioneering studies have undergone independent clinical validation. This review characterizes the current landscape of RNA-based liquid biopsy in lung cancer.
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