The central quantitative finding of the study is striking in its own right: across every organ examined, cancer cells carried approximately four times as many DNA mutations as the normal cells surrounding them. That cancer genomes are more heavily mutated than healthy genomes has long been known, but the mechanisms behind this elevation have remained contested. The traditional view held that the extra mutations arise largely because cancer-driving genes, once activated, destabilize the genome and generate further damage, or because rare catastrophic events shred the DNA of a developing tumor. The City of Hope and TGen team set out to test these ideas rigorously, and their results point toward a different and, in some ways, more unsettling explanation rooted in variation between people rather than within tumors.

To conduct the analysis, the researchers examined DNA from healthy and cancerous tissues in seven human organs: the bladder, colon, esophagus, liver, lung, prostate and stomach. They mined publicly available whole-genome and whole-exome sequencing data, drawing on hundreds of normal tissue samples and thousands of cancer samples. This scale makes the work one of the largest cross-organ comparisons of somatic mutation burden ever assembled. By applying consistent statistical methods across such a broad dataset, the team could ask not only whether tumors carry more mutations than healthy tissue, which they do in every organ studied with a median increase of more than fourfold, but also how mutation counts are distributed among apparently healthy people.

The answer to that second question surprised the investigators. Even after statistically accounting for age, which is well known to drive mutation accumulation, some healthy individuals had up to eight times more mutations in their organs than others. In other words, mutations do not build up at a uniform pace across the population. Instead, people appear to accumulate genetic changes in their tissues at markedly different rates, and those at the high end of this distribution can, while remaining cancer-free, carry mutation loads comparable to those found in patients diagnosed with the disease. Senior author Cristian Tomasetti, director of City of Hope’s Center for Cancer Prevention, Early Detection and Monitoring and a professor in the Early Detection and Prevention Division at TGen, said the research helps answer why some individuals get cancer, noting that these differences in mutations play a bigger role in cancer development than previously thought.

To make sense of the elevated mutation burden in tumors, the study formally evaluated three competing hypotheses. The first, which the authors call the classical hypothesis, proposes that cancer-driving mutations themselves lead to additional mutations, for example by impairing DNA repair machinery once key tumor suppressor genes are disabled. The second, the catastrophic hypothesis, invokes rare but extreme genomic events, such as chromothripsis, in which chromosomes shatter and reassemble in a single crisis, rapidly generating large numbers of mutations at once. The third, termed the tail hypothesis, shifts the focus from the tumor to the person: individuals whose tissues naturally accumulate mutations at higher rates sit in the tail of the population distribution and are therefore more likely to develop cancer in the first place.

When the researchers tested these explanations against the data, the tail hypothesis most consistently accounted for both observations that matter: the higher mutation burden seen inside tumors and the elevated mutation burden found in the normal tissues of people who went on to develop cancer. This pattern helps explain a long-standing puzzle in cancer genomics, namely why patients often carry more mutations not only in their tumors but also in their healthy cells. If a high personal mutation rate precedes the disease rather than resulting from it, the excess mutations in normal tissue are not a byproduct of the tumor but a signature of the underlying predisposition that made the tumor more likely to arise.

First author Sophie Pénisson, an associate professor in TGen’s Early Detection and Prevention Division, explained that 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. That reframing matters because it changes the target of inquiry. Rather than focusing exclusively on what happens inside a tumor after it begins to grow, researchers may need to understand the biological processes, from DNA repair efficiency to environmental exposures to stem cell division dynamics, that determine how quickly any given person’s cells accrue genetic damage over a lifetime.

The practical implications could be far-reaching. If mutation rate can be measured reliably in normal tissue, it could serve as a biomarker of cancer predisposition, complementing existing risk models based on family history, genetics and lifestyle. Tomasetti suggested that measuring a person’s mutation rate could become a critical way to identify those at higher risk and to develop more personalized strategies to prevent cancer. Such strategies might include intensified screening schedules, earlier and more frequent detection efforts, or preventive interventions tailored to individuals whose tissues show unusually rapid mutation accumulation. The study also underscores the value of large sequencing datasets generated for other purposes, since the analysis relied on publicly available data from hundreds of normal samples and thousands of tumors.

The work arrives amid growing interest in the field sometimes described as somatic mosaicism in healthy tissue, where sequencing of ostensibly normal organs has revealed that mutations are far more widespread than once assumed. What this study adds is a population-level perspective: the variation in mutation burden among healthy people is not a narrow technical footnote but a potentially decisive factor in who crosses the threshold into malignancy. The finding that some apparently healthy individuals carry cancer-level mutation burdens suggests that risk assessment could, in principle, move upstream, identifying high-risk profiles before tumors form and opening a window for prevention that current clinical practice rarely provides.

The study, titled Comprehensive Genomic Analysis of Normal and Cancer Cells Elucidates the Elevated Mutational Burden in Cancer, was supported by the Virginia Piper Charitable Trust, the Robert and Lynda Carter Altman Family Foundation Research Fund, the John Templeton Foundation and the National Cancer Institute. Several of the authors disclosed relationships with biotechnology and diagnostics companies outside the submitted work, including patents and consulting arrangements, as detailed in the journal’s conflict of interest statement. For now, the message for the field is conceptual rather than clinical: the race to cancer may be run at very different speeds in different people, and the pace of mutation accumulation in ordinary, healthy tissue may be one of the most important variables determining who ultimately reaches the finish line.

Subject of Research: Variation in somatic mutation rates in normal human tissues and its role in cancer risk

Article Title: City of Hope and TGen study finds hidden mutation rates may shape cancer risk

Article References: City of Hope and TGen study finds hidden mutation rates may shape cancer risk. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: cancer research, somatic mutations, mutation rate, genomics, cancer risk, TGen, City of Hope, Cancer Research journal, tail hypothesis, DNA damage, cancer prevention, whole-genome sequencing