LOS ANGELES AND PHOENIX (Oct. 1, 2026) — 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,” said senior author Cristian Tomasetti, Ph.D. , 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. “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.”
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:
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.
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The study “ Comprehensive Genomic Analysis of Normal and Cancer Cells Elucidates the Elevated Mutational Burden in Cancer ” was supported by the Virginia Piper Charitable Trust (grant TGen3003979), the Robert and Lynda Carter Altman Family Foundation Research Fund, the John Templeton Foundation (grant 62818) and the National Cancer Institute (grant U01CA271884).
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Conflict of interest notice: S Pénisson, K. Bates, and K. Lahouel report personal fees from C2T Biosciences Inc. outside the submitted work. B. Vogelstein reports other support from Haystack Oncology/Quest Diagnostics, Exact Sciences, Cage Pharma, Catalio Capital Management, Clasp Therapeutics, and Winnow Therapeutics during the conduct of the study, as well as a patent for D18678, for which disclosure of invention is pending, and a patent for C15959, for which JHU disclosure Q10 is pending, issued, licensed, and with royalties paid from Haystack Oncology/Quest Diagnostics and Exact Sciences. C. Tomasetti reports other support from C2T Biosciences Inc., PrognomiQ, and Haystack Oncology and personal fees from Bayer AG outside the submitted work, as well as a patent for CancerSEEK licensed and with royalties paid from Exact Sciences.
About TGen, part of City of Hope
Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based nonprofit organization dedicated to conducting groundbreaking research with life-changing results. TGen is part of City of Hope, a world-renowned independent research and treatment center for cancer, diabetes, and other life-threatening diseases. This precision medicine affiliation enables both institutes to complement each other in research and patient care, with City of Hope providing a significant clinical setting to advance scientific discoveries made by TGen. TGen is focused on helping patients with neurological disorders, cancer, diabetes, and infectious diseases through cutting-edge translational research (the process of rapidly moving research toward patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and complex rare diseases in adults and children. Working with collaborators in the scientific and medical communities worldwide, TGen makes a substantial contribution to helping patients through efficiency and effectiveness of the translational process. Follow on Facebook , Instagram , LinkedIn and Bluesky .
About City of Hope
City of Hope's mission is to make hope a reality for all touched by cancer and diabetes. Founded in 1913, City of Hope has grown into one of the largest and most advanced cancer research and treatment organizations in the United States, and one of the leading research centers for diabetes and other life-threatening illnesses. City of Hope research has been the basis for numerous breakthrough cancer medicines , as well as human synthetic insulin and monoclonal antibodies. With an independent, National Cancer Institute-designated comprehensive cancer center that is ranked among the nation’s top cancer centers by U.S. News & World Report at its core, City of Hope’s uniquely integrated model spans cancer care, research and development, academics and training, and a broad philanthropy program that powers its work. City of Hope’s growing national system includes its Los Angeles campus, Orange County, California, campus, a network of clinical care locations across Southern California and cancer treatment centers and outpatient facilities in the Atlanta, Chicago and Phoenix areas. City of Hope’s affiliated group of organizations includes Translational Genomics Research Institute and AccessHope TM . For more information about City of Hope, follow us on Facebook , X , YouTube , Instagram and LinkedIn .
Cancer Research
Experimental study
Human tissue samples
Comprehensive Genomic Analysis of Normal and Cancer Cells Elucidates the Elevated Mutational Burden in Cancer
1-Oct-2026
S Pénisson, K. Bates, and K. Lahouel report personal fees from C2T Biosciences Inc. outside the submitted work. B. Vogelstein reports other support from Haystack Oncology/Quest Diagnostics, Exact Sciences, Cage Pharma, Catalio Capital Management, Clasp Therapeutics, and Winnow Therapeutics during the conduct of the study, as well as a patent for D18678, for which disclosure of invention is pending, and a patent for C15959, for which JHU disclosure Q10 is pending, issued, licensed, and with royalties paid from Haystack Oncology/Quest Diagnostics and Exact Sciences. C. Tomasetti reports other support from C2T Biosciences Inc., PrognomiQ, and Haystack Oncology and personal fees from Bayer AG outside the submitted work, as well as a patent for CancerSEEK licensed and with royalties paid from Exact Sciences.