For a long time, cancer was explained almost exclusively as the result of genetic mutations—permanent errors in DNA that disrupt the normal functioning of cells. However, this view has changed significantly. Today we know that not everything depends on changes in genes themselves, but also on how those genes are regulated over time.
This is where epigenetics comes into play. When we talk about epigenetic changes, we refer to modifications that affect gene activity without altering the DNA sequence. In other words, the genetic “text” remains intact, but the cell decides which parts to read, which to ignore, and when to do so. This level of control allows the environment and a person’s biological experiences to profoundly influence cellular behavior.
From this perspective, the relationship between infections and cancer is no longer seen as exceptional or indirect. In fact, it is now recognized that approximately 10–15% of human cancers worldwide are associated with infections, a fact that forces us to rethink how we understand the origin of many tumors.
Chronic infections, such as those caused by certain bacteria and viruses, do not act as an immediate “switch” for cancer. Rather, they function as a silent and persistent factor. The immune system enters a prolonged state of alert, generating continuous inflammation that, over time, promotes the appearance of epigenetic alterations, including abnormal DNA methylation.
In this context, cells are not only forced to divide more rapidly to repair damaged tissues, but they also adapt to a hostile environment. This adaptation, largely mediated by epigenetic changes such as methylation, can become a dangerous advantage, as it allows the survival of cells with increasingly deficient control over their growth.
What Is DNA Methylation and Why Is It So Important?
DNA methylation is one of the main epigenetic mechanisms through which cells regulate gene activity. It can be imagined as a system of sticky notes placed on a book of instructions. The text—the genes—remains the same, but those notes indicate which pages can be read and which must remain closed.
Under normal conditions, this system is essential for development and healthy functioning of the organism. However, when methylation occurs in inappropriate regions of DNA, it can silence fundamental genes, such as those that repair DNA, control cell division, or eliminate damaged cells.
Chronic infections disrupt this control system. Constant inflammatory signals can induce cells to add methylation marks inappropriately, favoring an epigenetic state that increases the risk of cancerous transformation.
A key aspect is that these epigenetic changes are not always reversible. Even when the infection disappears, abnormal methylation can persist, acting as a “molecular memory” of the damage suffered.
The Key Concept: The “Epigenetic Field for Cancerization”
The concept of the epigenetic field for cancerization breaks with the traditional idea that cancer begins in a single isolated cell. In reality, an entire tissue can be epigenetically altered before any visible tumor appears.
This field forms when many cells accumulate similar epigenetic changes—such as abnormal DNA methylation patterns—due to a common exposure, for example a chronic infection or persistent inflammation. Although these cells are not yet cancerous, they are biologically closer to becoming cancer.
From a clinical point of view, this is revolutionary, as it allows cancer risk to be assessed before cancer exists, by analyzing epigenetic alterations in apparently normal tissues. It also helps explain why some patients develop multiple tumors in the same organ over time.
Figure 1. Cancer-associated pathogens promote aberrant DNA methylation through inflammation or direct epigenetic interference, creating tissue states prone to malignant transformation.
Helicobacter pylori and Gastric Cancer: A Paradigmatic Example
Helicobacter pylori is one of the best examples of how an infection can induce cancer through epigenetic mechanisms. This bacterium infects the stomach, generally during childhood, and can remain there for decades.
The chronic inflammation it causes induces progressive epigenetic changes, especially an increase in DNA methylation in protective genes, which alters the normal regulation of gastric tissue.
Specific Epigenetic Mechanisms
In addition to causing persistent inflammation, H. pylori stimulates the continuous production of inflammatory cytokines and reactive oxygen species. These signals activate enzymes responsible for DNA methylation, which add methyl groups to regions that control tumor suppressor genes.
As a result, genes responsible for repairing DNA or controlling cell growth are silenced, not by mutations, but by abnormal epigenetic regulation. These changes can appear even in early stages of infection, when no visible lesions yet exist.
A key finding is that these alterations are detected across large areas of the stomach, not only near lesions. This confirms that the entire tissue becomes epigenetically marked, reinforcing the concept of an epigenetic field.
Even after eradication of the bacterium, many of these marks persist, explaining why the risk of gastric cancer does not disappear immediately.
Viruses and Epigenetics: When the Invader Directly Alters Cellular Machinery
Some viruses not only generate inflammation, but also interact directly with the cell’s epigenetic mechanisms, including the systems that control DNA methylation.
Epstein–Barr Virus (EBV): Direct Epigenetic Reprogramming
Epstein–Barr virus is one of the clearest examples of a pathogen capable of actively manipulating cellular epigenetic machinery. It introduces viral proteins that activate enzymes responsible for DNA methylation.
This produces a state of hypermethylation, in which numerous tumor suppressor genes are coordinately silenced. In many EBV-associated tumors, the epigenetic alteration is so profound that it becomes the central characteristic of the cancer, even more relevant than genetic mutations.
Hepatitis B: Direct Viral Interaction With DNA Methylation
In hepatitis B, the virus not only causes chronic liver inflammation, but also directly interacts with epigenetic regulators in liver cells. Some viral proteins bind to factors that control DNA methylation, altering their function.
This favors abnormal methylation of genes that regulate cell proliferation and genomic stability. Over the years, these alterations accumulate, accompanying the progression from chronic hepatitis to cirrhosis and ultimately to liver cancer.
Hepatitis C: Persistent Inflammation and Indirect Epigenetic Dysregulation
Hepatitis C virus does not integrate into DNA, but it induces intense and prolonged chronic inflammation. Oxidative stress and inflammatory signals activate cellular mechanisms that alter DNA methylation in key genes.
Over time, liver tissue develops an epigenetic “memory” of inflammatory damage, creating an epigenetically unstable environment that is highly vulnerable to malignant transformation.
Human Papillomavirus (HPV) and Cervical Cancer
In persistent HPV infections, epigenetic changes appear early. The virus expresses proteins that interfere with normal cellular control mechanisms, facilitating alterations in DNA methylation in both the viral genome and the host cell.
As the infection persists, methylation increases in genes that regulate cell differentiation and the response to DNA damage. These changes precede the development of precancerous lesions, making them early markers of the risk of progression to cervical cancer.
This knowledge has enabled the development of more precise screening programs, based not only on the presence of the virus, but on its real epigenetic impact on the tissue.
Parasites and Epigenetic Carcinogenesis:
While bacteria and viruses are often highlighted in discussions of infection-related cancers, certain parasites are also classified as Group 1 (Class I) carcinogens by the International Agency for Research on Cancer (IARC). Notably, the liver flukes Opisthorchis viverrini and Clonorchis sinensis, as well as the bladder fluke Schistosoma haematobium, have well-established links to cancer development.
These parasites cause chronic, long-standing infections that result in persistent inflammation in affected tissues. O. viverrini and C. sinensis infect the bile ducts and are strongly associated with cholangiocarcinoma (bile duct cancer), while S. haematobium infects the urinary tract and is linked to squamous cell carcinoma of the bladder.
Beyond mechanical tissue damage and chronic inflammation, emerging evidence suggests that these parasites also contribute to carcinogenesis through epigenetic mechanisms. Continuous inflammatory signaling, oxidative stress, and parasite-derived molecules can disrupt host epigenetic regulation, including abnormal DNA methylation patterns in epithelial cells lining the bile ducts or bladder.
These alterations may silence tumor suppressor genes, alter pathways involved in DNA repair, and promote a tissue environment predisposed to malignant transformation. As with bacterial and viral infections, the result is not an immediate tumor, but the gradual establishment of an epigenetically altered field that increases long-term cancer risk.
Figure 2. Parasitic carcinogens such as Schistosoma haematobium, Opisthorchis viverrini, and Clonorchis sinensis promote tumorigenesis through persistent chronic inflammation, sustained oxidative stress, and aberrant DNA methylation, generating epigenetically altered tissue environments prone to malignant transformation.
A Common Pattern: Different Pathogens, One Epigenetic Language
Although each pathogen uses different strategies, all converge on the same outcome: sustained epigenetic alteration of host cells, especially through DNA methylation.
Whether through chronic inflammation, direct interaction with epigenetic regulators, or a combination of both, these infectious agents leave lasting epigenetic marks that increase tissue vulnerability to cancer.
Practical Applications: Prevention, Diagnosis, and Treatment
Epigenetics, and particularly the study of DNA methylation, offers concrete tools for cancer management:
Risk prediction: abnormal methylation in noncancerous tissues allows identification of individuals at higher future risk.
Early detection: epigenetic changes appear before many genetic mutations and can be detected in minimally invasive ways.
Prevention: reducing chronic infections and inflammation limits the accumulation of epigenetic alterations.
Treatment: epigenetic therapies aim to reverse changes such as abnormal methylation and restore normal function of key genes.
A New Vision of Cancer
Epigenetics shows us that cancer is not a sudden event, but the result of an accumulated biological history, in which infections, inflammation, and environment leave lasting marks, many of them in the form of DNA methylation.
Understanding these processes not only allows us to better understand cancer, but to anticipate its development, opening new opportunities for prevention, early diagnosis, and more precise treatments.
Main reference:
Hattori, N., & Ushijima, T. (2016). Epigenetic impact of infection on carcinogenesis: mechanisms and applications. Genome medicine, 8(1), 10. https://doi.org/10.1186/s13073-016-0267-2
Other references:
Moore, P. S., & Chang, Y. (2010). Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nature reviews. Cancer, 10(12), 878–889. https://doi.org/10.1038/nrc2961
de Martel, C., Ferlay, J., Franceschi, S., Vignat, J., Bray, F., Forman, D., & Plummer, M. (2012). Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. The Lancet. Oncology, 13(6), 607–615. https://doi.org/10.1016/S1470-2045(12)70137-7
Martin, D., & Gutkind, J. S. (2008). Human tumor-associated viruses and new insights into the molecular mechanisms of cancer. Oncogene, 27 Suppl 2, S31–S42. https://doi.org/10.1038/onc.2009.351
