Scientists Discover Hidden Class of Cancer-Specific RNAs Across 32 Tumor Types

What Are OncRNAs and How Were They Discovered?

The discovery began with a single enigmatic molecule called T3p, a small RNA first detected in breast cancer tissue in 2018. T3p was unusual because it did not match any known gene or genomic feature, yet it appeared consistently in tumor samples but was absent from normal breast tissue. This observation prompted researchers to ask whether similar uncharacterized RNAs might exist across other cancer types.

To answer this question, the research team conducted a comprehensive analysis of small RNA sequencing data from The Cancer Genome Atlas (TCGA), the largest publicly available collection of cancer genomic data. By systematically comparing RNA profiles between tumor and normal tissue across 32 different cancer types, they identified approximately 260,000 unique small RNAs that were present specifically in cancer cells — a vast hidden layer of cancer biology that had previously been overlooked because these molecules did not correspond to known genes or regulatory elements.

These cancer-specific RNAs, collectively termed oncRNAs, were found in every cancer type analyzed, from common cancers like breast, lung, and colorectal to rarer malignancies. Remarkably, the oncRNA profiles were highly specific — each cancer type and subtype produced a distinct oncRNA signature, like a molecular fingerprint. Machine learning algorithms trained on these signatures could accurately classify tumor type and subtype, suggesting immediate diagnostic applications.

How Could OncRNAs Transform Cancer Diagnosis?

One of the most clinically significant findings is that cancer cells actively release many oncRNAs into the bloodstream. This means these molecules can be detected in blood samples — a principle that underlies the rapidly developing field of liquid biopsy diagnostics. Unlike traditional tissue biopsies, which require invasive procedures and only sample a small portion of a tumor, liquid biopsies can capture molecular signals from the entire tumor burden and can be repeated over time to monitor disease progression.

In studies of breast cancer patients undergoing neoadjuvant chemotherapy (treatment given before surgery), circulating oncRNA levels provided valuable prognostic information. Patients with high levels of residual oncRNAs after treatment had nearly four-fold worse overall survival compared to those with low post-treatment oncRNA levels — even when controlling for standard clinical measures like tumor size, grade, and receptor status. This suggests oncRNA monitoring could help clinicians identify patients who need more aggressive treatment or alternative therapeutic approaches earlier than current methods allow.

The unique molecular fingerprints of different cancer types also raise the possibility of cancer-of-unknown-primary (CUP) diagnosis, a clinical scenario where metastatic cancer is detected but the original organ of origin cannot be determined. CUP accounts for approximately 3-5% of all cancer diagnoses, and identifying the primary site is crucial for selecting appropriate treatment. OncRNA profiling could potentially resolve these cases from a blood sample alone.

Can OncRNAs Be Targeted for Cancer Treatment?

Beyond diagnostics, the discovery revealed that some oncRNAs are not merely bystanders of cancer but active participants in tumor biology. In functional screening experiments using mouse models, approximately 5% of the oncRNAs tested produced clear biological effects on cancer behavior. Two breast cancer oncRNAs were particularly notable: they triggered epithelial-mesenchymal transition (EMT), a process by which cancer cells acquire the ability to invade surrounding tissues and spread to distant organs, and activated E2F target genes, which drive cell proliferation.

When these functional oncRNAs were introduced into breast cancer cells in mouse models, they significantly accelerated both tumor growth at the primary site and metastatic colonization of distant organs. This demonstrates that some oncRNAs are not merely biomarkers but genuine oncogenic drivers that could be therapeutically targeted. RNA-based therapies, including antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), are established drug modalities that could potentially be designed to neutralize specific oncRNAs.

The broader landscape of 260,000 oncRNAs likely contains many more functional molecules awaiting characterization. Researchers anticipate that systematic functional screens across multiple cancer types will identify additional therapeutic targets. The cancer specificity of oncRNAs — their absence from normal tissue — is particularly attractive from a therapeutic standpoint, as drugs targeting these molecules would be less likely to cause off-target effects in healthy cells compared to conventional chemotherapy.