In a disease as complex as cancer, two people can be exposed to the same risk factor for years and still experience completely different outcomes. One person who smokes may develop cancer, while another with apparently similar exposure never does. Something similar occurs with other environmental factors: not everyone exposed to ultraviolet radiation develops skin cancer, and not every cell subjected to DNA damage ultimately becomes a tumor.

For decades, this variability has been one of the major questions in cancer biology. We know that certain environmental factors increase risk, but exposure alone does not fully explain who will develop the disease or how a tumor will evolve.

Research published in Nature in July 2026 adds an important piece to this puzzle. The study proposes that our inherited genetics can profoundly influence what happens after a cell suffers DNA damage.

In other words, cancer may depend not only on which mutations arise, but also on the genetic context in which they occur.

 

The same exposure does not mean the same outcome

When we talk about risk factors, we often imagine a relatively simple relationship: a carcinogenic substance causes DNA damage, that damage generates mutations, and some of those mutations may promote the development of cancer.

The reality is considerably more complex.

Cancer is an evolutionary process. A cell may accumulate genetic alterations, but those alterations must provide some advantage that allows it to survive, proliferate, and eventually establish a population of tumor cells. A mutation that is beneficial in one cellular context may not provide the same advantage in another.

This idea helps explain a common observation in cancer epidemiology: individuals exposed to similar environmental factors can have very different risks. Some smokers never develop lung cancer, while some people who have never smoked do develop the disease.

This does not mean that smoking is safe. Tobacco use remains an established and preventable risk factor for multiple types of cancer. What the new study raises is a different question: why can the same source of damage produce different biological trajectories among individuals?

Part of the answer may lie in the genetics we inherit.

 

An experiment to “replay” cancer evolution

Studying this phenomenon directly in humans is extremely difficult. Every person has a different genetic history and has been exposed to unique combinations of diet, pollutants, infections, medications, habits, and other environmental factors.

The researchers therefore designed an experiment in which many of these variables could be controlled.

They used four genetically different groups of mice and exposed them to the same carcinogen, diethylnitrosamine, or DEN, a substance capable of causing DNA damage in liver cells. The age at exposure, the environment, and other experimental conditions were kept controlled. The scientists then analyzed hundreds of tumors using whole-genome sequencing, transcriptome analysis, and histopathology. In total, the study characterized 581 experimentally induced tumors.

The approach was powerful because it allowed the researchers to ask a relatively simple question: if the initial damage is similar, does cancer evolve in the same way?

The answer was NO.

 

Genetics changed how quickly tumors appeared

One of the first differences involved the amount of time required for tumors to develop.

In one of the genetic backgrounds studied, tumors consistently appeared around 25 weeks after exposure. In another, they appeared around 36 weeks; in another, approximately 38 weeks; and in another, around 78 weeks. Spontaneous tumors in untreated animals also followed a similar pattern of susceptibility among the different groups.

This means that even though the animals received a controlled carcinogenic exposure, their genetic predisposition significantly altered the trajectory toward cancer.

But an even more interesting finding emerged.

The most susceptible animals were not necessarily those whose tumors contained the greatest number of mutations. In fact, the burden of DNA substitutions was higher in some of the groups that took longer to develop tumors. This challenges an overly simplistic interpretation of cancer: more mutations do not automatically mean greater risk.

What matters is which mutations occur, when they occur, and, above all, what advantages they provide within a particular organism.

 

Not all mutations have the same effect in everyone

The scientists observed that approximately 95% of the tumors carried mutations that were likely to activate genes in the MAPK pathway, particularly Braf, Hras, Egfr, and Kras. This pathway controls processes related to cell growth and proliferation and is frequently altered in cancer.

In other words, tumors from the different groups tended to converge on a similar biological pathway.

But they did not reach that point in the same way.

Depending on the animal’s genetic background, the frequency with which particular driver genes appeared changed. Even when the same gene was affected, different specific alterations could be selected.

It is like several travelers trying to reach the same city, but their starting point determines which road is most favorable.

The genetic background would act as part of that landscape: some mutations encounter conditions that favor their expansion, while others may provide little advantage or even disappear.

 

The dialogue between inherited genes and new mutations

This is where one of the study’s most important concepts comes into play: epistasis between germline variants and somatic mutations.

Germline variants are those we inherit and that are present from birth. Somatic mutations, in contrast, arise during our lifetime in specific cells as a consequence of replication errors, aging, or environmental exposures.

The researchers found evidence that these two types of genetic information can interact.

An acquired mutation capable of driving cancer may have different consequences depending on the genetic background in which it appears. The study identified interactions involving important cellular systems, including the p53, TGF-β, and PPAR pathways, which participate in processes such as cell division, differentiation, inflammation, and cell death.

Therefore, a mutation should not be imagined as an independent switch that simply turns cancer on.

Its effect depends on the system in which it is embedded.

 

Some organisms may need fewer “steps” to initiate a tumor

Another observation is particularly illustrative.

In tumors from most of the groups, at least two driver mutations were generally identified. In contrast, tumors from the most susceptible group had a median of only one.

The authors suggest that this could mean that this genetic background required fewer additional changes for a cell to initiate or maintain tumor growth.

Imagine two different locks. One requires three mechanisms to be activated simultaneously before it opens; the other requires only one. The external stimulus may be exactly the same, but the ease with which the final result is reached is different.

Applied to cancer, this could help explain why individual susceptibility does not depend exclusively on how much carcinogenic exposure a person receives.

 

 

Figure 1. Environmental factors can cause DNA damage, but inherited genetic differences may influence which driver mutations are required for cancer to develop and persist.

 

Does this mean we can predict who will develop cancer?

No.

This point is fundamental because the study was conducted in mice using an experimental model of liver cancer. It does not demonstrate that there is currently a genetic test capable of determining which smoker will develop cancer, nor does it allow the times, genes, or probabilities observed in the study to be directly transferred to humans.

The researchers themselves emphasize the need for further studies before determining exactly what these findings mean for people.

What the study does provide is experimental evidence for a biological principle: even relatively modest genetic differences can modify the selective pressures acting during tumor development and alter both cancer susceptibility and its evolution.

And that has important implications.

Currently, many prevention strategies are based primarily on known risk factors: age, smoking, sun exposure, family history, certain infections, or occupational exposures.

In the future, gaining a better understanding of how these factors interact with thousands of inherited genetic variants could allow considerably more precise risk estimates.

The findings could also have therapeutic implications. If genetic background influences which mutations are selected and how particular alterations affect cellular behavior, it could help explain why apparently similar tumors follow different trajectories or respond differently to certain treatments. The authors suggest that these interactions between inherited genetics and tumor mutations could be relevant to future prognostic and predictive tools.

The research also reinforces the importance of including genetically diverse populations in cancer studies. If certain variants influence tumor evolution, studying overly homogeneous populations could overlook an important part of cancer biology.

 

Cancer does not depend on a single piece

For a long time, we have tried to understand cancer by looking for individual culprits: a mutation, a carcinogen, a gene, or a molecular pathway. Modern research reveals a much more dynamic picture.

Environmental factors can cause damage. Mutations can provide new abilities to a cell. But the fate of those mutations depends on the biological context in which they arise.

Inherited genetics may help define which evolutionary paths are available to a tumor. In the experiments, the different genetic backgrounds frequently converged on activation of the MAPK pathway, but they used different mutations, displayed different evolutionary dynamics, and showed marked differences in susceptibility.

That is why the question, “Why does one exposed person develop cancer while another does not?” will probably never have a single answer.

The environment matters. Mutations matter. Age and other biological factors matter. And, as this research shows, the genome we inherit can also profoundly modify what happens after damage occurs.

Understanding these interactions could bring us closer to an oncology in which cancer prevention, surveillance, and treatment depend less on assuming that every organism responds in the same way and more on understanding the particular biology of each individual.

 

Main reference:

Aitken, S. J., Connor, F., Feig, C., Rayner, T. F., Lukk, M., Luft, J., Aitken, S., Arnedo-Pac, C., Hayes, J. F., Nicholson, M. D., Ewing, A., Sundaram, V., Verburg, J. C., Connelly, J., Anderson, C. J., Behm, M., Campbell, S., Daunesse, M., Kaiser, V. B., … Odom, D. T. (2026). Genetic background sets the trajectory of experimental cancer evolution. Nature. https://doi.org/10.1038/s41586-026-10821-z

 

Other references:

Fisher, R., Pusztai, L., & Swanton, C. (2013). Cancer heterogeneity: implications for targeted therapeutics. British journal of cancer, 108(3), 479–485. https://doi.org/10.1038/bjc.2012.581

Alexandrov, L. B., Kim, J., Haradhvala, N. J., Huang, M. N., Tian Ng, A. W., Wu, Y., Boot, A., Covington, K. R., Gordenin, D. A., Bergstrom, E. N., Islam, S. M. A., Lopez-Bigas, N., Klimczak, L. J., McPherson, J. R., Morganella, S., Sabarinathan, R., Wheeler, D. A., Mustonen, V., PCAWG Mutational Signatures Working Group, Getz, G., … PCAWG Consortium (2020). The repertoire of mutational signatures in human cancer. Nature, 578(7793), 94–101. https://doi.org/10.1038/s41586-020-1943-3