Blood RNA Biomarkers Linked to Colorectal Cancer

In a groundbreaking study published in BMC Cancer, researchers have unveiled compelling associations between blood-based RNA biomarkers and circulating tumour cells (CTCs) in patients with previously untreated metastatic colorectal cancer (mCRC). This discovery holds the promise of transforming prognostication and personalized treatment strategies in one of the world’s deadliest cancers.

Metastatic colorectal cancer remains a formidable clinical challenge, often characterized by late diagnosis and poor survival rates. Traditionally, the enumeration of circulating tumour cells — cancer cells that have shed from the primary tumour into the bloodstream — has emerged as a robust prognostic indicator. The innovative angle of this new study lies in coupling CTC counts with the expression profiles of selected messenger RNAs (mRNAs) and microRNAs (miRNAs) in whole blood, aiming to decode more nuanced molecular signals that could refine patient risk stratification.

The researchers conducted a comprehensive analysis involving 151 patients who were previously screened for enrollment in two clinical trials, VISNÚ1 and VISNÚ2. Using real-time quantitative PCR (qPCR), the team quantified the expression of specific RNAs implicated in metastasis directly from whole blood samples. The study employed the CellSearch system — an FDA-approved technology — to accurately enumerate basal circulating tumour cells (bCTCs), focusing on their potential correlations with RNA expression, tumour genetic mutations, and clinical outcomes.

One of the most salient findings was the significant association between bCTC count and the expression of AGR2 mRNA. AGR2, or anterior gradient 2, is a protein linked to tumour growth and metastatic potential, and its elevated mRNA levels in the blood appear entwined with the burden of circulating tumour cells. This correlation was consistent across the entire patient cohort, underscoring AGR2’s potential as a systemic biomarker reflective of tumour dissemination.

The study further delved into subgroups, revealing that AGR2, alongside ADAR1 and LGR5, showed significant associations with bCTC numbers in patients harboring three or more circulating tumour cells. ADAR1, an RNA editing enzyme, has been recognized for its roles in cancer immune evasion and RNA stability, while LGR5 is known as a stemness marker indicative of cancer cell self-renewal. The simultaneous link between these RNAs and higher bCTC counts suggests a complex interplay between tumour biology, stem cell-like properties, and metastatic dissemination.

Interestingly, when focussing on tumours with wild-type (native) RAS, BRAF, and PIK3CA genes, the correlation between these RNA biomarkers and CTCs remained prominent, highlighting their potential utility in a specific genetic context. By contrast, in patients with mutations in these oncogenes, the relationships shifted. No direct associations with bCTC counts emerged; instead, an intriguing pattern of RNA expression changes was observed.

Specifically, mutated tumours showed an upregulation of miR-224-5p and LGR5, denoting enhanced stemness features and possibly increased metastatic competence. Simultaneously, there was a downregulation of CD274, coded as PD-L1, an immune regulatory molecule crucial in cancer’s evasion of immune surveillance. These alterations underscore the distinct biological pathways active in genetically mutant tumours and may have implications for tailoring immunotherapeutic approaches.

A major highlight of the study was the revelation that lower blood levels of miR-106a-5p and miR-26a-5p microRNAs were significantly associated with shorter overall survival. These miRNAs—which regulate gene networks involved in cell proliferation and apoptosis—could serve as independent prognostic markers beyond traditional clinical and pathological factors. Their robust association with poor prognosis, confirmed through multivariate statistical analyses, opens a window for new blood-based assays to predict patient outcomes.

The integration of whole blood RNA profiling with CTC enumeration embodies a novel analytical framework that could revolutionize the monitoring and management of metastatic colorectal cancer. By capturing both circulating tumour burden and molecular signatures simultaneously, this approach offers a dynamic picture of tumour biology in real-time, surpassing the limitations of tissue biopsies that often fail to reflect tumour heterogeneity and evolution.

Moreover, the implications extend to personalized medicine. Understanding how RNA biomarkers correlate with mutational status offers clues to the underlying tumorigenic mechanisms, potentially guiding targeted therapeutic decisions. For example, identifying patients with elevated AGR2 and LGR5 in the context of wild-type mutational status may prioritize them for treatments that disrupt cancer stemness or metastatic seeding.

The findings also contribute to a growing body of evidence linking microRNAs to cancer prognosis, resistance, and metastasis. MicroRNAs like miR-106a-5p and miR-26a-5p are emerging as vital modulators of oncogenic pathways, and their circulating levels are conveniently accessible for non-invasive monitoring. Future studies can explore whether modulating these miRNAs therapeutically could alter disease trajectory.

This study’s design, anchored by data from prospective clinical trials (NCT01640405 and NCT01640444), lends robustness and clinical relevance to the conclusions. The researchers meticulously validated RNA expression and CTC counts, linking molecular phenomena to clinical endpoints, thus reinforcing the translational value of their discoveries.

Despite the promise, challenges remain. The sensitivity and specificity of RNA biomarkers in heterogeneous patient populations need further validation across diverse cohorts and clinical settings. Additionally, deciphering the causal relationships between RNA expression, mutational landscapes, and tumour dissemination demands longitudinal studies and functional assays.

Nevertheless, this integrative approach exemplifies the future of oncology research, where multifaceted biomarkers combine to capture the complexity of cancer progression. The potential to stratify patients accurately based on blood RNAs and CTCs could facilitate adaptive treatment algorithms, improving survival and quality of life for many facing metastatic colorectal cancer.

As efforts accelerate towards liquid biopsies in oncology, the identification of AGR2, ADAR1, LGR5, miR-224-5p, miR-106a-5p, and miR-26a-5p as critical blood-based markers heralds a new era of precision diagnostics. Their clinical deployment could enable oncologists to detect aggressive disease early, monitor therapeutic response dynamically, and intervene promptly.

The study ultimately underscores the heterogeneity of metastatic colorectal cancer and the importance of personalized molecular profiling. As the landscape of cancer treatment becomes increasingly tailored, insights derived from circulating biomarkers promise to enhance prognostication and guide innovative therapies that could change the course of this deadly disease.

Looking forward, integrating such RNA biomarkers into clinical workflows hinges on developing standardized assays and platforms amenable to routine practice. Collaborations between researchers, clinicians, and diagnostic companies will be pivotal to translate these findings from bench to bedside.

In conclusion, this landmark research represents a significant leap towards understanding the molecular underpinnings of circulating tumour cells and RNA biomarker signatures in metastatic colorectal cancer. By illuminating previously uncharted interactions between circulating biomarkers and cancer genetics, the study opens pathways to novel diagnostic approaches, better patient stratification, and ultimately improved clinical outcomes.

Subject of Research: Associations between blood RNA biomarkers, circulating tumour cells, tumour mutations, and prognosis in untreated metastatic colorectal cancer patients

Article Title: Associations of blood RNA biomarkers and circulating tumour cells in patients with previously untreated metastatic colorectal cancer

Article References:
Valladares-Ayerbes, M., Toledano-Fonseca, M., Graña, B. et al. Associations of blood RNA biomarkers and circulating tumour cells in patients with previously untreated metastatic colorectal cancer. BMC Cancer 25, 743 (2025). https://doi.org/10.1186/s12885-025-14098-9

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14098-9

Tags: blood RNA biomarkersCellSearch technology in cancer detectioncirculating tumor cells analysisclinical trials in cancer researchcolorectal cancer prognosisinnovative cancer diagnosticsmessenger RNAs in cancermetastatic colorectal cancermicroRNAs in colorectal cancerpersonalized cancer treatmentreal-time quantitative PCR in oncologyrisk stratification in mCRC