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Diagnostics Genetics and epigenetics, Liquid biopsy, Oncology, Precision medicine, Screening and monitoring, Technology and innovation

Thinking Outside the (Genome) Box

At a Glance

  • Access to accurate and effective cancer diagnostic technologies is variable, leading to delays in detection and treatment and poor clinical outcomes
  • Conventional diagnostics are costly, invasive, and time-consuming, often requiring complex specialist procedures or hospitalization
  • Epigenetic biomarkers are highly specific for disease state and tissue type and can be detected upstream of genetic alterations
  • By combining minimally invasive sampling techniques with the precision and sensitivity of epigenetic analysis, we can detect cancer early and begin timely therapeutic intervention

Across the globe, cancer causes one in every six deaths. Mortality is most commonly a consequence of malignant disease of the lung, colon, stomach, liver, or breast tissue (1). Disease progression, accompanied by the metastatic spread of tumor cells to other tissues within the body, remains the primary cause of death and disability among those with cancer (2). To reduce this burden, early detection and intervention are critical. We must improve survival rates and lower morbidity – but we must do so wisely, optimizing the use of expensive specialist medicines, health resources, and procedures.

A diagnostic defecit

Conventional diagnostics are limited by suboptimal accuracy. They are also expensive to deliver, requiring specialist skills and services. Inadequate access to resources or technology and the intrusive nature of many investigative techniques (such as tissue biopsy, colonoscopy, or pleural fluid sampling) hinder disease detection and significantly impact patients’ quality of life. How can we improve upon these approaches? Minimally invasive techniques that employ highly sensitive biomarkers for early-stage disease and allow regular screening using a simple blood or saliva sample would support a simple, practical, and cost-effective approach that might be more acceptable to patients. And with increased access to testing and increased willingness to be screened, such a technique could potentially identify cancers early enough to improve the odds of treatment success. It would also facilitate ongoing monitoring during or after treatment – giving patients the best chance of having disease progression identified and halted, or receiving prompt treatment in the case of relapse.

In recent years, the rapidly evolving field of epigenetics has driven transformative advances in research regarding the fundamental biological processes controlling human development, disease, and aging. Innovations in this area have the potential to revolutionize cancer diagnostics beyond the capabilities of traditional genetic screening, delivering exceptional levels of accuracy and enabling detection ahead of symptomatic disease.

Better biomarkers for disease

Epigenetic modifications are highly potent and specific chemical groups within genomic DNA or RNA nucleotide sequences and histone proteins (3). These modifications, which include methylation, phosphorylation, acetylation, and more, do not alter the underlying sequence of genomic DNA itself; rather, they influence the behavior and regulation of genes.

Disruption or dysregulation of the epigenetic machinery can have disastrous consequences.

Epigenetic modifications are heritable and can also be added, removed, or altered in response to external factors. Lifestyle (for example, smoking or diet), environment (for example, pollutants), and other stressors can influence the dynamic structure and function of the epigenome. Why? Epigenetic changes may provide an evolutionary advantage or drive molecular processes and cascades associated with aging and disease. The epigenome maintains a delicate balance of chemical modifications essential for multiple cellular processes in healthy biological systems. However, disruption or dysregulation of the epigenetic machinery can have disastrous consequences; mutations within epigenetic regulators are prevalent across all cancers and have also been linked with a wide range of neurological, immunological, and metabolic diseases (3,4).

Specific epigenetic patterns or signatures have become important biomarkers for disease. Pioneering technologies that allow these stable biomarkers to be mapped and quantified have revealed that it is possible to detect high-intensity signals from clinical samples. Epigenetic biomarkers are also highly specific for disease state and tissue type, allowing accurate assessment of disease progression and tissue of origin.

Figure 1. 5mC (left) and 5hmC (right) are critical epigenetic modifications involved in the regulation of molecular pathways required for normal cellular function. Dysregulation of the 5mC and 5hmC pathways is associated with pathogenesis and a number of aggressive cancers.


Among the most important epigenetic modifications characterized to date, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) (see Figure 1) have been proven to play a pivotal role in the development of cancers and other serious diseases (5, 6, 7, 8). Regulation of the molecular pathways associated with these chemical changes is critical to maintaining normal cellular function and avoiding pathogenesis. For example, the Ten-Eleven Translocation (TET) family of enzymes converts 5mC to 5hmC in DNA. Loss of function or changes in the expression of TET enzymes correlate with abnormalities in cytosine methylation that are associated with a number of aggressive cancers (7,8).

Changes in 5mC and 5hmC are also predictors of very early-stage cancer transformation. Research in glioblastoma cells has demonstrated that epigenetic alterations associated with oncogenic pathways can be detected in neighboring non-tumor cells, even when these cells appear genetically “normal” (9). This discovery highlights the potential value of epigenetic signatures in cancer screening programs – as robust biomarkers for early-stage disease that can be detected well before genomic changes are apparent (see Table 1).

Table 1. Key features of epigenetic biomarkers and their potential diagnostic or clinical benefits.


In addition, epigenetic biomarkers can provide insights into the risk of metastasis, tumor recurrence, and overall prognosis. Further research, again in glioblastoma cells, has shown that levels of 5hmC are important in the regulation of disease-critical genes. Global reduction in 5hmC across the genome tends to be associated with poor clinical outcomes and reduced survival (5). Using such information, clinicians may be able to stratify patients according to risk and epigenetic profile to offer more accurate prognoses and guide appropriate treatment.

Therapeutic resistance is an ongoing challenge in the successful management of cancers. Specific signatures associated with drug resistance have been identified within the epigenome and can occur in the absence of genetic alterations (3,10). Individuals exhibiting resistance biomarkers may have a greater risk of treatment failure and therefore be better candidates for alternative therapeutic options. Regular testing would allow resistance issues to be identified quickly, allowing patients to move to the most effective treatment options as soon as they are needed, rather than having to work through a rigid treatment regimen after it has lost its effectiveness. This kind of personalized approach would allow patients to avoid chemotherapies that are associated with significant toxicities but, due to the individual’s molecular/epigenetic profile, offer little or no therapeutic benefit. The ultimate outcome? Healthier patients, easier treatment, and better use of costly health resources.

Harnessing the power of epigenetics

Over time, cancers tend to evolve with disease progression or in response to environmental factors and the body’s own immune response (11,12). Disease heterogeneity presents a further barrier to appropriate treatment selection and tailoring of management strategies. Traditional approaches to sampling and diagnosis, such as solid tumor biopsy, are generally unable to provide a full picture of heterogeneity because analysis is limited by the range of cancerous cell types present in the “snapshot” sample. In contrast, analysis of circulating tumor DNA (ctDNA) or cell-free DNA (cfDNA) from liquid biopsy samples taken at regular intervals could provide a more comprehensive view of cellular evolution. After all, liquid biopsy makes serial sampling and screening easier to implement in routine practice, allowing samples to be taken during treatment or follow-up to guide disease management, gain a better understanding of how a cancer is changing, and identify issues or concerns while they can still be addressed.

To obtain valuable diagnostic information from these samples, we need meaningful signals from even small quantities of cfDNA or ctDNA – so technologies must offer a high level of sensitivity and specificity. Notably, not all biomarkers can be identified and measured using traditional genetic research techniques; critical epigenetic markers or signatures are missed when laboratory scientists look solely at the genome. To detect them, we need epigenetics-focused technologies with adequate signal strength to find markers in samples containing exceptionally low ctDNA concentrations.

Why make the leap?

In a modern healthcare environment, where funding and resources are usually limited or restricted, cancer treatment and ongoing management represent a significant financial burden. Technologies that offer liquid biopsy sampling alongside automated epigenetic analyses may help to reduce healthcare costs on a number of levels. For instance, liquid biopsy sample collection does not require hospitalization or specialist involvement; support staff can take samples during routine visits, which allows cancer specialists to make more efficient use of their time by focusing on treatment, rather than on diagnostic sample collection. Additionally, disease identified early using epigenetic biomarkers is likely to require less intensive therapeutic approaches, reducing patients’ risk of treatment-related complications or toxicity issues. Finally, epigenetic biomarkers can guide or individualize appropriate treatment selection according to the individual patient’s profile – supporting optimal therapy and cost-effective prescribing.

Liquid biopsy and epigenetic platforms offer a powerful combination of minimally invasive and maximally informative diagnostics, without sacrificing simplicity and practicality. Essential information concerning the nature and stage of disease, prognosis, risk, and drug resistance can be elucidated using potent epigenetic biomarkers identified from a simple blood test. This forward-thinking approach has the potential to shift the oncology treatment paradigm towards earlier and more effective treatment of disease for the benefit of patients, clinicians and healthcare systems.

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  1. World Health Organization, “Cancer facts” (2018). Available at: Accessed October 17, 2018.
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About the Author
Jason Mellad

Jason Mellad is former Chief Executive Officer at Cambridge Epigenetix. He has recently taken on a new venture and, as of November 15, 2018, Suman Shirodkar has taken over as Chief Executive Officer of Cambridge Epigenetix Ltd., Cambridge, UK.

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