What explains the extra mutations?

The team evaluated three possible explanations for the elevated mutation burden seen in cancer:

• The classical hypothesis: cancer-driving mutations themselves cause additional mutations to accumulate.
• The catastrophic hypothesis: rare but extreme genomic events rapidly generate large numbers of mutations at once.
• The tail hypothesis: some individuals simply accumulate mutations at a higher rate throughout their tissues, and those individuals are more likely to develop cancer.

Among the three, the tail hypothesis most consistently explained the data. It accounted both for the higher mutation burden observed in tumors and for the elevated mutation burden found in the normal, non-cancerous tissues of people with cancer. This helps explain a puzzle that earlier models could not: people who develop cancer tend to have more mutations not only in their tumors but also in their healthy cells.

"Study results pointed to a new explanation for why this happens. Instead of most extra mutations being caused only by cancer-driving genes or rare DNA damage, the findings suggest that some people accumulate mutations at a higher rate in their tissues," said first author Sophie Pénisson, Ph.D., an associate professor in TGen's Early Detection and Prevention Division.

How large are the differences between people?

Age matters — older people accumulate more mutations — but it does not explain the whole picture. Even after accounting for age, the differences between individuals remained dramatic.

"Even after accounting for age, some healthy people had up to eight times more mutations than others, showing that mutations build up at very different rates from person to person, something only the tail hypothesis can explain. Understanding why some people accumulate mutations faster than others could change how we identify cancer risk," Pénisson said.

An eightfold gap in mutation burden between two healthy people of the same age is substantial. It suggests that hidden, person-specific mutation rates — not just inherited genes or environmental exposures — may be a meaningful contributor to cancer risk.

What could this change in cancer prevention?

The findings open the door to improved approaches to cancer risk assessment and prevention. If mutation rate varies so widely from person to person, measuring that rate could become a tool for spotting people who need closer monitoring.

"Measuring a person's mutation rate could become a critical way to identify people at higher risk and develop more personalized strategies to prevent cancer," Tomasetti said.

The study also highlights the importance of understanding the biological processes that drive higher mutation rates in some individuals, and it could help guide future research on earlier detection, prevention and more personalized treatments.

What are the limits of the study?

The findings are preliminary in important ways. The analysis relied on publicly available sequencing data, and while the sample was large — hundreds of normal tissue samples and thousands of cancer samples across seven organs — the study describes associations rather than proven causes. The researchers did not directly demonstrate that high-mutation healthy individuals went on to develop cancer; that causal link will require long-term follow-up studies.

Still, the work offers a new framework for a long-standing question in cancer biology: why the disease strikes some people and spares others. The suggestion that a measurable, variable trait — a person's underlying mutation rate — helps determine that risk is a step toward prevention strategies tailored to the individual rather than the average patient.

The paper, by Sophie Pénisson and colleagues, appears in Cancer Research (DOI: 10.1158/0008-5472.can-26-0117). City of Hope, one of the largest cancer research and treatment organizations in the United States, is ranked among the nation's leading cancer centers by U.S. News & World Report.