DNA mutations transformed precision oncology. But mutations are only one way cancer tells its story. Researchers are now looking beyond the genome to understand cancer through complementary molecular biomarkers.

For decades, DNA mutations have been the foundation of precision oncology. By identifying the genetic changes that drive cancer, DNA testing can help assess inherited cancer risk, guide targeted therapies, and monitor disease through liquid biopsy.[1,2]

These mutations are permanent changes to the genetic code. But cancer biology extends far beyond DNA sequence alone.

Cells also control when genes are switched on, which genes are actively expressed, how proteins are produced, and how energy is used. Each layer provides different insights into cancer, forming the basis of multi-omics.

Table 1. DNA mutations remain the cornerstone of precision oncology, while complementary biomarkers provide additional insights into how cancers develop, evolve, and respond to treatment.

DNA Methylation: Controlling Gene Activity

Cancer can influence every step of this process. It does not only change the DNA sequence. It also changes how that DNA is used. One of the earliest control points is DNA methylation, which determines whether a gene is switched on or off without changing the DNA sequence itself.

DNA methylation is an epigenetic mechanism that regulates whether genes are active without altering the underlying genetic code. While DNA mutations permanently change the sequence, methylation influences which genes are expressed. Because abnormal methylation patterns often appear early in cancer development, they have become an important area of research for multi-cancer early detection and predicting a cancer's tissue of origin.[3]

DNA explains what changed.

Methylation helps explain how those changes are regulated.

Messenger RNA: Showing Which Genes Are Active

If DNA is the blueprint, messenger RNA (mRNA) reflects the instructions the cell is actively following.

RNA testing is already part of routine cancer care. In tissue, it is widely used to identify clinically important gene fusions that help guide treatment decisions. More recently this has been extended to blood-based liquid biopsy to detect 1 in 3 more clinically relevant gene fusions with a combined ctDNA + ctRNA approach.[4,5]

Studies have shown that circulating tumor RNA (ctRNA) can provide information beyond DNA alone, capturing gene expression, immune activity, and features of the tumor microenvironment.[6] In some patients, informative ctRNA signals remain detectable even when circulating tumor DNA cannot be identified, demonstrating that RNA can complement DNA rather than simply duplicate it.[6]

As liquid biopsy continues to evolve, DNA and RNA are increasingly viewed as complementary biomarkers that together provide a more complete picture of tumor biology.

MicroRNA: Small Molecules With Big Potential

Not all RNA molecules carry genetic instructions.

MicroRNAs (miRNAs) are short RNA molecules that regulate how much protein is ultimately produced from messenger RNA. Unlike mRNA, they are remarkably stable in blood because they are protected within protein complexes and other circulating particles, making them attractive candidates for blood-based cancer detection.[7]

Thousands of cancer-associated miRNA signatures have been described, but translating these discoveries into clinical tests has proven difficult. Differences in blood collection, RNA extraction, normalization methods, and data analysis can all influence results, making it challenging to reproduce findings consistently across laboratories.[7]

Improving assay standardization remains one of the key steps toward broader clinical adoption.

Proteins: Measuring What Cells Are Doing

Genes encode the instructions, but proteins carry out the biology.

Protein biomarkers such as PSA, CA-125, CEA, and AFP have been used in oncology for decades and remain valuable for monitoring treatment response and disease recurrence in selected cancers.

Unlike DNA or RNA, proteins reflect the functional state of cells. However, protein levels can also change because of inflammation, infection, or other non-cancer conditions, limiting their use as stand-alone diagnostic tests. For this reason, protein biomarkers are often interpreted alongside imaging, clinical findings, and genomic testing.[8]

Metabolites: Following Cancer's Chemistry

Cancer cells rewire the way they generate and use energy.

One familiar example is glucose metabolism, which forms the basis of FDG-PET imaging used routinely in oncology.[9] Researchers are now exploring whether changes in circulating metabolites, including amino acids, lipids, and organic acids, could also serve as blood-based biomarkers for early detection, treatment monitoring, and identifying treatment resistance.[9]

Unlike DNA, metabolism is influenced by many factors beyond cancer, including diet, exercise, medications, and the gut microbiome. Interpreting these signals remains challenging, but metabolomics offers another promising window into cancer biology.

Looking Beyond DNA

DNA mutations transformed precision oncology and remain the foundation of modern molecular diagnostics.

Today, researchers are building on that foundation by studying the biological layers that sit above DNA, from gene regulation and RNA expression to proteins and metabolism.

Each biomarker reveals something different.

Together, they offer a more complete understanding of how cancers develop, evolve, and respond to treatment.

That is the promise of multi-omics. Not replacing DNA, but complementing it with additional biological insights that may help detect cancer earlier, monitor disease more precisely, and guide more informed clinical decisions.

Cancer is not written in one molecular language.

The future of precision oncology will come from understanding more of them.

References

1. National Cancer Institute. Biomarker Testing for Cancer Treatment. Updated 2021.

2. National Cancer Institute. Genetic Testing for Inherited Cancer Risk. Updated 2024.

3. National Cancer Institute Center for Cancer Research. Cancer Epigenetics. Accessed 2026.

4. Heeke S, et al. JTO Clin Res Rep. 2025:100795.

5. Poh J, et al. J Clin Oncol. 2025;43(16):suppl.3016.

6. Pek M, et al. J Clin Oncol. 2026;44(19): suppl. 167.

7. Singh V, et al. EJIFCC 2024; 35(4):265–284.

8. Savas I and Coskun A. Biomolecules 2025; 15(7): 1011. 

9. Wang W, et al. Biomark Res. 2023;11:66. doi: 10.1186/s40364-023-00507-3