Genetics and epigenetics in tumor diagnosis, therapeutics, and prognosis: an editorial
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Cancer is a public health problem globally and is the second-leading cause of death. In the US, it is estimated that there will be ~2,114,850 new cancer patients and 626,140 patient deaths in 2026[1]. Epigenetics studies the reversible and heritable alterations, including histone modification, DNA methylation, chromatin remodeling, and non-coding RNA, that affect gene function without changing DNA sequence. These alterations could drive cancer development and progression alongside genetic mutations in cancers. Unlike irreversible genetic mutations, these modifications can often be reversed with drugs or are druggable, thus allowing development of novel epigenetic drugs (epidrugs) therapy that reprograms cancer cells back to normal functions. Cancer epigenetics could offer a powerful, non-invasive frontier in oncology for early tumor detection, disease monitoring, risk assessment, precise prognostics, and reversing therapeutic resistance.
TUMOR DETECTION: NON-INVASIVE AND ULTRA-EARLY DIAGNOSIS
Epigenetic alterations, particularly DNA methylation, appear early in carcinogenesis, even earlier than physical lesions detectable by imaging. Because these signatures are stable and detectable in body fluids (blood, urine, stool), they can serve as excellent, non-invasive liquid biopsy markers for early diagnosis, disease monitoring, and screening. Liquid biopsy is a non-invasive and highly sensitive cancer screening approach that detects the methylation patterns of circulating tumor DNA or circulating cell-free DNA (cfDNA) in blood, urine, saliva, or feces. Technologies such as flow cytometry and next-generation sequencing (NGS), mass spectrometry-based approaches, droplet digital PCR (ddPCR), particularly circulating tumor cell analysis (enriched by flow cytometry), cfDNA sequencing, and emerging epigenetic and fragmentomic profiling are in different phases of development that have the potential to revolutionize the approach to detect and treat cancers[2-4]. Likewise, advances in fragmentomics and histone modification profiling are revealing new dimensions of tumor biology that can be captured through liquid biopsy, allowing clinicians to monitor treatment response and measure minimal residual disease (MRD) with unprecedented precision.
Multi-cancer detection (MCD) and Multi-cancer early detection (MCED)
MCD and MCED are new diagnostic tools utilizing epigenomic features to screen for multiple cancers at once, which significantly improve the early detection rate[5]. Similar to innovative liquid biopsies, MCD/MCED tests can analyze a single blood sample for tumor-derived DNA, RNA, or proteins to detect multiple cancer types simultaneously, often before symptoms appear. These tests aim to improve survival rates by catching cancers earlier, particularly those lacking standard screening methods.
While promising, these tests are not diagnostic and require follow-up confirmation. Currently, there are tests that are still in development or undergoing clinical trials, with some, such as EPISEEK and Galleri® MCED, which is commercially available but has not yet been approved by the U.S. Food and Drug Administration (FDA). EPISEEK is a groundbreaking MCED test that uses a simple blood draw to monitor DNA changes associated with over 60 types of cancer. Galleri® test is used for adults aged 50 and older with an elevated cancer risk[6].
Examples of tests that are currently in clinical application include the Cologuard and ConfirmMDx. Cologuard is an FDA-approved colorectal cancer screening technology based on fecal DNA methylation. The test can detect aberrantly methylated promoters of genes including Bone Morphogenetic Protein 3 and N-myc Downstream-Regulated Gene 4 (https://www.cologuard.com/). Cologuard Plus test was also developed and FDA-approved to reduce false positives. It also scans for mutant KRAS and total human hemoglobin. ConfirmMDx works for prostate cancer at the DNA level to help identify undetected cancers
MRD assessment technology
In recent years, the landscape of cancer diagnostics has been fundamentally transformed by the emerging MRD assessment technology. The technology utilizes epigenetic signatures to define tumor subtypes, distinguish benign from malignant tissues, and monitor cancer recurrence.
MRD assessments can be peripheral blood-based, bone marrow-based, and imaging-based techniques. Bone marrow-based next-generation flow cytometry and NGS with a minimum sensitivity of 10-5 (1 aberrant cell per 100,000 total cells analyzed) remain the current standard for MRD assessment in cancers, particularly in multiple myeloma (MM)[2]. Mass spectrometry-based methods, such as intact protein mass spectrometry (MALDI-TOF assays like MASS-FIX and EXENT) and clonotypic peptide mass spectrometry (EasyM and M-Insight), have emerged as highly sensitive peripheral blood-based MRD assessment tools for relatively non-invasive dynamic MRD detection. Newer technologies such as circulating tumor cell analysis using enriched flow cytometry, cfDNA sequencing, ddPCR, and emerging epigenetic and fragmentomic profiling are also under extensive study and have the potential to revolutionize detection and treatment of cancers. Clinical trials exploring the role of MRD in guiding cancer therapy are ongoing and are expected to identify the optimal technique for MRD monitoring in clinical practice.
CANCER TREATMENT: RESTARTING THE CANCER SUPPRESSION SWITCH
Since epigenetic alterations are not permanent modifications to the DNA sequences, they can be druggable, making them a key focus for cancer therapy. The so-called epidrugs aim to reset the gene expression program of tumor cells and restore the activity of tumor suppressor genes or inhibit oncogenes by targeting epigenetic marks. Epidrugs include histone deacetylase inhibitors (HDACi), DNA methyltransferase inhibitors (DNMTi), histone methyltransferase inhibitors (HMTi), and bromodomain and extra-terminal motif protein inhibitors (BETi)[7]. By inhibiting "writers" (such as DNMTs), "erasers" (such as HDACs), or "readers" (such as BET proteins), abnormally silenced tumor suppressor genes can be reactivated, or oncogenes can be inactivated.
Epidrugs
Epidrugs are a class of therapeutic agents that modify the structure of DNA and chromatin to reverse abnormal gene expression without altering the underlying DNA sequences. Primarily used in cancer treatment to reactivate silenced tumor suppressor genes, these compounds target enzymes like histone deacetylases (HDACs) and DNA methyltransferases (DNMTs). Table 1 shows epigenetic-based drugs that are approved by the FDA. These drugs in the treatment of cancer were also recently summarized by Suraweera et al.[8] and Scandolara et al.[9], and we also updated the newest information.
Epidrugs that are FDA-approved for cancer therapeutics
| Drug name | Target | Approved | Year | Approved cancer indication | Reference |
| Azacitidine (Onureg, Vidaza) | DNA methyltransferase (DNMT) | Yes | 2004 | Acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and juvenile myelomonocytic leukemia | [8,9] |
| Decitabine (Dacogen) | DNMT | Yes | 2006 | AML, MDS and CMML | [8,9] |
| Vorinostat (SAHA) | Histone deacetylase (HDAC) | Yes | 2006 | Cutaneous T-cell lymphoma (CTCL) | [8,9] |
| Romidepsin (FK288) | HDAC | Yes | 2009 | CTCL | [8,9] |
| Belinostat (PXD101) | HDAC | Yes | 2014 | Peripheral T-cell lymphoma (PTCL) | [8,9] |
| Panobinostat (LBH589) | HDAC | Yes | 2015 | Multiple myeloma and CTCL | [8,9] |
| Tazemetostat (Tazverik) | Histone methyl transferase EZH2 | Yes | 2020 | Epithelioid sarcoma and follicular lymphoma | [8,9] |
| Enasidenib (IDHIFA) | Metabolic epigenetic regulator (IDH2) | Yes | 2017 | IDH2-mutant AML | [9] |
| Ivosidenib (Tibsovo) | Metabolic epigenetic regulator (IDH1) | Yes | 2018 | IDH1-mutant AML | [9] |
| Olutasidenib (Rezlidhia) | IDH1 | Yes | 2022 | IDH1-mutant AML | [9] |
| Ivosidenib/Azacitidine | IDH1/DNMT1 | Yes | 2022 | IDH1-mutated AML | [9] |
| Voranigo (Vorasidenib) | IDH1/IDH2 | Yes | 2024 | Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation | [10] |
| Revumenib (Revuforj) | Menin-KMT2A interaction/NPM1 mutation | Yes | 2024/2025 | Refractory acute leukemia with KMT2A translocations (KMT2Ar) and NPM1 mutation | [11,12] |
| Ziftomenib (Komzifti) | Menin-NPM1 mutation | Yes | 2025 | Relapsed or refractory AML with NPM1 mutation | [13] |
| Dordaviprone (Modeyso) | H3K27M mutation | Yes | 2025 | A protease activator harboring an H3K27M mutation for various cancers | [14] |
| Treosulfan (Grafapex) | DNA cross-linking in cancer cells | Yes | 2025 | In combination with fludarabine as a preparative regimen for allogeneic hematopoietic stem cell transplantation for AML and MDS | [15] |
Currently, there are not many FDA-approved epidrugs. Although Treosulfan belongs to the DNA alkylating agents and inhibits tumor cells by directly modifying the DNA structure, this kind of drug could be classified as genetic/epigenetic modification therapy.
Additionally, since chemotherapy faces drug resistance, natural small molecules or compounds such as Isoflavonoids can be an interesting alternative in cancer therapeutics[16,17]. Studies should investigate the potential of natural and synthetic compounds as anti-cancer agents including epidrugs[18-20].
Combinational therapy and reversal of drug resistance
Furthermore, synergistic effects are provided for therapy and reversal of drug resistance. Epidrugs are often used in combination with chemotherapy or immunotherapy to activate the antitumor immune response by inducing a "viral mimicry" response or to make drug-resistant cells sensitive to traditional therapies again. For example, DNMTi can enhance tumor immunogenicity by inducing a "viral mimicry" effect (activating endogenous retroviruses), thereby improving the efficacy of PD-1/PD-L1 inhibitors.
Epigenetic interventions can also reverse cancer drug resistance by altering the epigenetic landscape (episensitization), and thus restoring sensitivity to conventional chemo- or endocrine therapies. In breast cancer, epigenetic interventions can resensitize tumor cells that have developed resistance to conventional chemotherapy or endocrine therapy. For example, HDACi combined with tamoxifen can induce apoptosis in drug-resistant cells in breast cancer[21].
Challenges in solid tumors
While effective in hematological malignancies, targeting epigenetics in solid tumors faces challenges such as poor drug delivery, resistance/off-target effects, high cellular heterogeneity, and the need for more specific predictive biomarkers.
PROGNOSTIC ASSESSMENT: ACCURATE PREDICTION OF RISK AND EFFICACY
Prognostics is the clinical assessment of a patient's treatment outcomes, including the probability of cancer progression, recurrence, or survival. Epigenetic markers can more accurately predict a patient's cancer progression, therapy response, survival and relapse risk than traditional staging[7].
For example, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation acts as a critical biomarker in GBM. Specifically, silencing MGMT gene due to promoter methylation leads to decreased DNA repair capacity, enhanced sensitivity to temozolomide (TMZ) chemotherapy, and results in improved overall survival[22]. Thus, MGMT promoter methylation serves as a key predictor of response to TMZ chemotherapy in GBM.
Clinically, Graded Prognostic Assessment (GPA) for brain metastases[23] or Palliative Prognostic Score
CONCLUSION AND PERSPECTIVES
Multi-omics integration, computational models, and artificial intelligence (AI) contribute to the development of novel strategies for early cancer detection, risk stratification, MRD monitoring, and precise prognostics. Computational approaches are revolutionizing the field, with deep learning frameworks now capable of predicting metastatic potential from primary tumor methylation data, while AI-driven deconvolution techniques enable the dissection of tumor methylation profiles to uncover the immune and stromal components of the tumor microenvironment, which is key to predicting treatment response. cfDNA methylation signatures have emerged as highly sensitive biomarkers for MCED offering a promising route for non-invasive screening across multiple tumor types. Similarly, advances in fragmentomics and histone modification profiling are revealing new dimensions of tumor biology that can be performed through liquid biopsy, allowing clinicians to monitor treatment response and detect MRD with unprecedented precision. Cell-free chromatin state tracing (cf-EpiTracing) may provide early diagnosis, molecular subtyping and prognostic prediction by revealing disease origin and therapy responses[25].
CRISPR-based epigenome editing will provide a powerful experimental toolkit to validate candidate regulatory regions and epigenetic drivers identified in large-scale datasets. Tang et al.[26] systematically reviewed the advances using CRISPR-based molecular biosensing for pathogen detection and early tumor screening. They summarized the technological evolution of device integration, including automated and closed microfluidics to portable systems to achieve point-of-care testing.
Mapping the epigenetic regulatory networks that drive cancer initiation, progression, and therapy resistance remains a critical challenge. In gastrointestinal cancer, Huang et al.[27] systematically illustrated the epigenetic dysregulation for providing hints in clinical translation. G-quadruplexes (G4s) are non-canonical secondary structures formed by guanine-rich DNA or RNA strands by Hoogsteen hydrogen bonds that help control gene replication, transcription, and RNA translation. DHX36, a member of the DEAD/H box superfamily, is a main helicase that unwinds G4s of target genes[28,29]. Abnormal G4 regulation by helicases should be linked to cancer pathways and progression epigenetically, making them targets for new diagnostics, prognostics, and treatments[30,31]. The DHX36-m6A-G4 axis might play roles in health and disease in an epigenetic way[31,32].
Single-cell multi-omics (such as scRNA-seq + scATAC-seq) combined with bulk data will dissect the intratumoral heterogeneity and identify epigenetically distinct cell states. Li et al.[33] reviewed precision management in chronic myeloid leukemia by single-cell sequencing. Furthermore, advanced techniques like ATAC-seq and ChIPmentation allow for rapid assessment of chromatin accessibility, providing high-precision, personalized diagnostics. Emerging technologies such as third-generation sequencing and spatial epigenomics now enable direct and spatial measurements of DNA methylation and chromatin accessibility, opening new possibilities for correlating epigenetic signatures with tissue architecture.
The field of pharmacoepigenomics is rapidly advancing, leveraging epigenetic markers to predict response to targeted epigenetic therapies and guide combination treatment strategies. Computational epigenetics can accelerate the identification of new therapeutic candidates by exploiting known epigenetic signatures and drug-epigenome interactions.
DECLARATIONS
Acknowledgments
The authors would like to thank colleagues from the Research Center for Preclinical Medicine of Southwest Medical University for their help.
Authors’ contributions
Conceptualization, data acquisition and writing: Fu J, Wu RC
Availability of data and materials
Not applicable.
AI and AI-assisted tools statement
No.
Financial support and sponsorship
Not applicable.
Conflicts of interest
Fu J is a Section Editor of the Journal of Translational Genetics and Genomics and also serves as a Guest Editor for the Special Issue "Power of Epigenetics in Tumor Detection, Treatment, and Prognosis", Fu J was not involved in any steps of editorial processing, notably including reviewers' selection, manuscript handling and decision making. Wu RC declares that there are no conflicts of interest.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Copyright
© The Author(s) 2026.
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Fu J, Wu RC. Genetics and epigenetics in tumor diagnosis, therapeutics, and prognosis: an editorial. J Transl Genet Genom. 2026;10:567-73. https://dx.doi.org/10.20517/jtgg.2026.122
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