July 28, 2026, 4:01 pm | Read time: 5 minutes
Is it pure luck or a particularly diligent repair system that seems to protect some smokers from cancer? Researchers have now made an exciting new discovery in mice: Depending on the genetic makeup, tumors either run out of time before they can become deadly—or they strike immediately.
In Some People, a Single Genetic Defect Leads to Cancer
It has long been known that smoking drastically increases the risk of lung cancer. Estimates suggest that about 85 percent of all deaths from bronchial carcinoma are directly related to tobacco use.1 However, a medical mystery remains unsolved: Why do only about 10 to 20 percent of lifelong smokers actually develop lung cancer, while others remain unaffected despite decades of smoking?
An important first clue that some smokers are “spared” from cancer due to a genetic peculiarity was provided four years ago by researchers at the Albert Einstein College of Medicine.2 At that time, it was suspected that some people handle smoking better than others. Now researchers show: Behind this may be a genetic barrier that determines how many critical mutations are needed before cancer can develop.
Others Need Multiple Genetic Errors to Potentially Develop Cancer
The latest insight comes from Dr. Sarah J. Aitken at the Yale Cancer Center. To study this fundamental mechanism independently of smoking, researchers simulated the development of liver cancer hundreds of times in mice.
The idea behind it: Some genetic backgrounds apparently allow cancer cells to grow after just a single critical mutation. Others require several such changes. As a result, cancer develops much later—or sometimes not at all.
Our inherited genetic makeup not only determines our cancer risk but also guides the timeline of cancer development. According to the researchers, this principle applies to all people and all types of cancer, not just smokers. Smokers, however, are a particularly illustrative example of this mechanism.
While the preliminary study by U.S. lung specialist Simon Spivack in 2022 actually examined 33 human subjects (smokers and non-smokers), Aitken deliberately chose a different approach for the study now published in the journal “Nature.”3
Researchers Repeated “Evolution” of Cancer in Mice
In humans, it’s difficult to say whether genes or lifestyle are the deciding factors in why some develop cancer under the same pollutant exposure, and others do not. Aitken and her team therefore used a mouse model. They selected four different groups of mice that genetically differ from each other as much as humans from different parts of the world. Since all mice were kept the same, researchers could rule out environmental factors as the cause. Differences between the animals had to be due to their genes.
They did not expose the (exclusively male) mice to cigarette smoke but administered a substance that reliably triggers liver cancer. This allowed them to repeatedly study cancer development under the same conditions. Subsequently, the researchers closely examined 581 tumors. Using the latest genetic technology, they decoded the complete genome of each tumor and searched for all genetic changes that occurred during cancer development.
While mice of the genetic group C3H immediately developed cancer, other mice (genetic CAROLI group) proved to be survival artists: For a tumor to grow in these animals at all, more genetic changes were needed. These genetic changes give other cells the crucial push to multiply uncontrollably, thus driving the formation and growth of a tumor (known as driver mutations).
Whether a driver mutation occurs in a cell is based on chance. By waiting many times for tumors to develop, researchers found that in C3H mice, a single genetic error was enough to cause cancer. In CAROLI mice, however, two or more of these random driver mutations were simultaneously needed for cancer to develop. This number is considered a biological barrier by the researchers.
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Barrier in Cancer Development
In cancer-prone mice, cancer developed on average after just 25 weeks. When the biological barrier was higher (meaning several genetic errors were needed to start tumor growth), it took an average of 78 weeks. Sometimes, these resistant mice did not develop cancer at all.
Many cancer cells in resistant mice had doubled their entire genome. With this “trick,” cancer cells apparently withstand additional genetic errors better than others. The evidence for this whole-genome duplication was also found by the researchers. The volume of the nuclei of those cancer cells was measurably enlarged to store two complete sets of genetic material.
The particularly cancer-prone C3H mice and the resistant CAROLI mice were extreme opposites. The other two mouse groups (BL6 and CAST) also generally required two or more driver mutations to develop cancer. Interestingly, in BL6 mice, the immune system apparently recognizes cells with mutations and destroys them before they can cause harm.
Although the results of the newly published animal study cannot be directly applied to humans, it is very likely that this biological barrier also exists in humans. Aitken: “The same genetic change can lead to completely different clinical outcomes in two people—depending on the biological baggage they carry.”
The results from the 2022 study supported this assumption. At that time, researchers observed that mutations in lung tissue in some smokers stagnated after 23 pack-years—meaning the consumption of one pack of cigarettes daily over 23 years.
Results Have High Relevance for Humans, According to Researchers
The researchers describe their model as a powerful tool to understand the timeline of cancer, which in humans is often masked by factors like diet or lifestyle. In fact, the researchers are calling for a rethink in cancer research. Sarah Aitken points out that the interaction between inherited genetic material and newly acquired mutations is currently not considered.
Treatment of the individual must be rethought. It must be tailored as precisely as possible to the person. It is no longer enough to just look at whether a gene (such as through smoking) is mutated. The entire genetic background of the patient must be known to predict how aggressive the cancer will be and which therapy will best help this person.