Varying mutation rates in healthy organs explain cancer risk

A new study by scientists at City of Hope^® and TGen, part of City of Hope, found surprisingly large differences in the number of mutations present in organs of healthy individuals. Some study participants had a similar number of mutations as is typically found in cancer patients. These results provide an explanation for why some individuals ultimately end up with cancer, opening the door to improved approaches for cancer risk assessment and prevention.

City of Hope is one of the largest and most advanced cancer research and treatment organizations in the country and is ranked among the nation's leading cancer centers by U.S. News & World Report.

The results, published today in Cancer Research, a journal of the American Association for Cancer Research, provide a systematic comparison of mutation burdens in organs from both healthy individuals and those with cancers, showing that cancer cells carry approximately four times as many DNA mutations as normal cells. More importantly, the study compared the number of mutations present in organs of healthy individuals, finding differences larger than expected.

This research helps answer why some individuals get cancer. We studied how mutations vary from person to person. We found evidence that even among healthy individuals, there are strikingly large differences in the number of mutations present in their organs, with some apparently healthy people carrying as many mutations as those found in people with cancer, making it much more probable for the former to get to cancer. These differences in mutations play a bigger role in cancer development than we previously thought."

Cristian Tomasetti, Ph.D., senior author, director of City of Hope's Center for Cancer Prevention, Early Detection and Monitoring and professor in the Early Detection and Prevention Division at TGen

The study provides a new way to understand why some people are more likely to get cancer than others and highlights the importance of better understanding the biological processes that drive higher mutation rates. It could also help guide future research on earlier detection, prevention and more personalized treatments.

The researchers studied DNA from healthy and cancerous tissues in seven human organs: the bladder, colon, esophagus, liver, lung, prostate and stomach. They analyzed publicly available whole-genome and whole-exome sequencing data from hundreds of normal tissue samples and thousands of cancer samples.

Their work represents one of the largest comparisons of mutations conducted to date. Across every organ studied, cancer cells showed a statistically significant increase in mutation burden, with a median increase of more than fourfold compared with healthy tissue.

"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 mutation rate in their tissues," said first author Sophie Pénisson, Ph.D., associate professor in TGen's Early Detection and Prevention Division.

The study evaluated three possible explanations for the increased mutation burden:

• The classical hypothesis, where cancer-driving mutations lead to additional mutations.
• The catastrophic hypothesis, where rare but extreme genomic events rapidly generate large numbers of mutations.
• The tail hypothesis, where individuals with higher mutation rates are more likely to develop cancer.

Among these, the tail hypothesis most consistently explained both the higher mutation burden observed in cancer and the elevated mutation burden found in the normal tissues from people with cancer. This finding could help explain why people who develop cancer often have more mutations not only in their tumors, but also in their healthy cells.

"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," said Dr. Pénisson.

"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," said Dr. Tomasetti.