In a major study published on October 8 in Nature, scientists from the Wellcome Sanger Institute and the TwinsUK study at King's College London mapped how harmful DNA mutations accumulate across the entire sperm genome as men age.

The results open new avenues for studying how environmental and lifestyle factors might influence the genetic health of future generations.

In tissues that constantly renew, mutations (changes in DNA) can give some cells an advantage, allowing them to multiply faster than others. These groups of identical "clonal" cells then expand, eventually outnumbering their neighbors. While most mutations in the body's ordinary cells (such as those in organs, connective tissue, and bone) are not passed to children, mutations in sperm and egg cells can be inherited. Until recently, however, scientists lacked the precise tools to measure how strongly certain mutations are favored in sperm.

To overcome this, the team used NanoSeq¹, a highly accurate DNA sequencing technology, to analyze sperm from 81 healthy men aged 24 to 75.^2,3 The samples came from the TwinsUK cohort, the UK's largest adult twin registry, which provided a well-documented and diverse population for comparison.

The data revealed that about 2 percent of sperm from men in their early 30s carried disease-causing mutations. This proportion increased to 3-5 percent in men aged 43 to 74. Among 70-year-old participants, 4.5 percent of sperm contained harmful mutations, showing a clear link between age and genetic risk to offspring.

The increase is not caused solely by random DNA errors accumulating over time. Instead, a subtle form of natural selection within the testes appears to give certain mutations a reproductive advantage, allowing them to become more common during sperm formation.

Researchers pinpointed 40 genes that seem to benefit from this process, many of which are tied to serious neurodevelopmental disorders in children and inherited cancer risks. While 13 of these genes were previously known to be involved, the new study shows the phenomenon affects many more genes linked to cell growth and development than scientists once realized.

Although the number of sperm carrying harmful mutations rises with age, not every one of these mutations leads to conception or a healthy pregnancy. Some may prevent fertilization or normal embryo development, while others could cause miscarriage. More studies are needed to determine how the growing number of sperm mutations affects children's health outcomes.

By revealing how mutations arise and are shaped by selection within sperm, the researchers hope to refine reproductive risk assessments and better understand how genetics, lifestyle, and environment interact across generations.

In a complementary study, also published in Nature,⁴ scientists from Harvard Medical School and the Sanger Institute investigated the same phenomenon from a different angle by looking at mutations already passed on to children, rather than those measured directly in sperm. By analyzing DNA from over 54,000 parent-child trios and 800,000 healthy individuals, the team identified more than 30 genes where mutations give sperm cells a competitive edge, again including many linked to rare developmental disorders and cancer, and many overlapping the set of genes observed directly in sperm. The study found that these mutations can increase sperm mutation rates roughly 500-fold which helps explain why some rare genetic disorders appear when parents do not carry the mutations in their own DNA. Interestingly, the study notes that as these mutations are common in the sperm, it may look like some genes cause false-positive disease association due to the elevated mutation rate rather than a true disease link. The work highlights how natural selection within sperm can be directly observed in the DNA of children, influencing their chances of inheriting certain genetic disorders.

Dr. Matthew Neville, first author from the Wellcome Sanger Institute, said: "We expected to find some evidence of selection shaping mutations in sperm. What surprised us was just how much it drives up the number of sperm carrying mutations linked to serious diseases."

Professor Matt Hurles, Director of the Wellcome Sanger Institute and co-author, said: "Our findings reveal a hidden genetic risk that increases with paternal age. Some changes in DNA not only survive but thrive within the testes, meaning that fathers who conceive later in life may unknowingly have a higher risk of passing on a harmful mutation to their children."

Professor Kerrin Small, co-author and Scientific Director of the TwinsUK study at King's College London, said: "We are incredibly grateful to the twins who took part in this study. By working with the TwinsUK cohort, we could include valuable longitudinal samples linked to rich health and genetic information, allowing us to explore how mutations accumulate and evolve with age in healthy individuals. This collaboration highlights the power of large, population-based cohorts for advancing our understanding of human development and inheritance."

Dr. Raheleh Rahbari, senior author and Group Leader at the Wellcome Sanger Institute, said: "There's a common assumption that because the germline has a low mutation rate, it is well protected. But in reality, the male germline is a dynamic environment where natural selection can favour harmful mutations, sometimes with consequences for the next generation."

This research is part-funded by Wellcome. A full list of funders can be found in the acknowledgements in the publication.

Notes

1. Launched in 2021 by the Wellcome Sanger Institute, nanorate sequencing (NanoSeq), is a method that makes it possible to study how genetic changes occur in human tissue whilst maintaining high accuracy. The method reduces error rates to less than five errors per billion calls which is much lower than typical somatic mutation rates.
2. Blood samples were taken to ensure that mutations studied in sperm were only in sperm cells.
3. The researchers split the data into age groups: 26-42 years (younger men), 43-58 years (middle-aged), and 59-74 years (older men).
4. Sunyaev, S. et al. (2025) 'Hotspots of human mutation point to clonal expansions in spermatogonia'. Nature. DOI: 10.1038/s41586-025-09579-7
5. In a complementary study (Lawson, A. et al) researchers at the Sanger Institute have reported using targeted NanoSeq to uncover hidden mutations that occur naturally in bodies, providing insight into the earliest steps of cancer development and the role of mutations in different diseases. This team also collaborated with the TwinsUK study at King's College London. They applied targeted NanoSeq to cheek and blood samples from more than 1,000 volunteers to uncover a rich landscape of mutations in healthy tissues, which can be applied to future research into aging and diseases. Targeted NanoSeq is the same tool used in the above study. DOI: 10.1038/s41586-025-09584-w

Researchers tested a therapy that combines enzalutamide, an existing cancer drug, with standard hormone therapy. This approach significantly lowered death rates among men whose prostate cancer came back after initial treatment and who had few remaining options. The study findings were published in The New England Journal of Medicine (NEJM) and presented at the European Society for Medical Oncology Congress (ESMO) on Oct. 19 in Berlin.

"After initial treatment, some patients see their prostate cancer come back in an aggressive way and are at risk for their disease to spread quickly," said Stephen Freedland, MD, director of the Center for Integrated Research in Cancer and Lifestyle at Cedars-Sinai Cancer and co-principal investigator of the study. "Hormone therapy, which is what we've been offering patients for 30 years, has not improved survival and neither has anything else. That makes these findings a real game changer."

The international clinical trial followed more than 1,000 men from 244 medical centers across 17 countries. All participants had high-risk biochemically recurrent prostate cancer, a condition where prostate specific antigen (PSA) levels rise rapidly after surgery or radiation. PSA is a protein used to monitor prostate cancer activity, and a sharp increase after treatment often signals that the disease is likely to return and spread, often to the bones or spine.

"We know these patients are at high risk of developing metastatic disease and dying of their cancer unless we offer a meaningful treatment option," said Freedland, professor of Urology and the Warschaw, Robertson, Law Families Chair in Prostate Cancer.

Participants were randomly assigned to receive either hormone therapy alone, enzalutamide alone, or both together. After eight years of follow-up, those who received the combination therapy had a 40.3% lower risk of death compared to those in the other two groups, according to Freedland.

"This clinical trial, one of many that Cedars-Sinai Cancer has offered to its patients, is an example of the translational work being done by our physician-scientists," said Robert Figlin, MD, interim director of Cedars-Sinai Cancer. "The result will be improved treatment and better outcomes for patients everywhere."

Freedland added that enzalutamide is already approved by the Food and Drug Administration and included in National Comprehensive Cancer Network treatment guidelines based on earlier research by the same team. He said these new results will likely strengthen those recommendations and help establish the enzalutamide and hormone therapy combination as the new standard of care for patients with high-risk biochemically recurrent prostate cancer.

"These important findings identify a treatment that prolongs survival in men with aggressive prostate cancer," said Hyung Kim, MD, a urologic oncologist and chair of the Department of Urology at Cedars-Sinai. "The latest analysis complements previous studies that found enzalutamide significantly improved survival in other prostate cancer settings, and will change how we take care of our patients."

Funding: The study was sponsored by Pfizer Inc. and Astellas Pharma Inc., the co-developers of enzalutamide.

Disclosures: Stephen J. Freedland reports being a consultant to Astellas Pharma Inc., AstraZeneca, Bayer, Eli Lilly, Johnson & Johnson Innovative Medicine (formerly Janssen), Merck, Novartis, Pfizer Inc., Sanofi, Sumitomo Pharma America, Inc. (formerly Myovant Sciences, Inc.), and Tolmar.

Scientists from the University of Florida and the University of Texas MD Anderson Cancer Center describe this as a milestone in more than a decade of work developing mRNA-based treatments that activate the body's immune defenses against cancer. Building on an earlier UF study, the results represent an important step toward creating a universal cancer vaccine capable of enhancing the effects of immunotherapy.

The analysis, which examined medical records from over 1,000 MD Anderson patients, is still preliminary. However, if upcoming randomized clinical trials confirm these results, the impact on cancer care could be profound.

"The implications are extraordinary -- this could revolutionize the entire field of oncologic care," said senior researcher Elias Sayour, M.D., Ph.D., a UF Health pediatric oncologist and the Stop Children's Cancer/Bonnie R. Freeman Professor for Pediatric Oncology Research. "We could design an even better nonspecific vaccine to mobilize and reset the immune response, in a way that could essentially be a universal, off-the-shelf cancer vaccine for all cancer patients."

Jeff Coller, Ph.D., a leading mRNA expert at Johns Hopkins University, noted that the findings highlight yet another way Operation Warp Speed (the U.S. government's rapid COVID-19 vaccine initiative) continues to benefit lives in "unique and unexpected ways."

"The results from this study demonstrate how powerful mRNA medicines truly are and that they are revolutionizing our treatment of cancer," Coller said.

Presented today (October 19) at the 2025 European Society for Medical Oncology Congress in Berlin, the study builds on eight years of Sayour's research combining lipid nanoparticles with mRNA. Messenger RNA, or mRNA, is present in every cell and carries the instructions for making proteins.

In July, Sayour's laboratory made an unexpected discovery: to trigger a strong immune attack on cancer, it was not necessary to target a specific tumor protein. Instead, they could simply stimulate the immune system to respond as if it were fighting a viral infection.

By pairing their experimental "nonspecific" mRNA vaccine with immune checkpoint inhibitors -- common cancer drugs that help the immune system recognize and destroy tumors -- the researchers observed a powerful antitumor response in mice. This experimental vaccine was not specific to COVID or any other virus or cancer but used similar technology to COVID-19 vaccines.

That breakthrough inspired former UF researcher and current MD Anderson scientist Adam Grippin, M.D., Ph.D., to ask a key question: Could the COVID-19 mRNA vaccine have a similar immune-boosting effect in cancer patients?

To explore that idea, the team analyzed data from patients with Stage 3 and 4 non-small cell lung cancer and metastatic melanoma treated at MD Anderson between 2019 and 2023.

Their findings showed that patients who received a COVID mRNA vaccine within 100 days of starting immunotherapy survived significantly longer than those who did not.

According to Sayour, the most striking improvements occurred in patients who, based on tumor biology and other factors, were not expected to respond strongly to immunotherapy.

Although these results are from an observational study and require confirmation through a randomized clinical trial, researchers emphasize their potential importance.

Despite the need for further validation, Sayour described the discovery as pivotal for the future of cancer treatment.

"Although not yet proven to be causal, this is the type of treatment benefit that we strive for and hope to see with therapeutic interventions -- but rarely do," said Duane Mitchell, M.D., Ph.D., Grippin's doctoral mentor and director of the UF Clinical and Translational Science Institute. "I think the urgency and importance of doing the confirmatory work can't be overstated."

In lung and skin cancers, doctors commonly engage the immune system with drugs designed to "release the brakes" and recognize and attack cancer cells more effectively. In advanced disease stages, however, most patients don't respond well and often have exhausted other treatment options like radiation, surgery and chemotherapy.

The new study involved records of 180 advanced lung cancer patients who received a COVID vaccine within a 100-day period before or after starting immunotherapy drugs and 704 treated with the same drugs who did not receive the vaccine. Getting the vaccine was associated with a near doubling of median survival, from 20.6 months to 37.3 months.

Of the metastatic melanoma patients, 43 received a vaccine within 100 days of initiating immunotherapy, while 167 patients did not receive a vaccine. With the vaccine, median survival increased from 26.7 months to a range of 30 to 40 months; at the time the data were collected, some patients were still alive, meaning the vaccine effect could be even stronger.

Receiving non-mRNA pneumonia or flu vaccines resulted in no changes in longevity.

To back their findings, UF researchers then used mouse models to pair immunotherapy drugs with an mRNA vaccine targeted specifically at COVID spike protein. Those experiments showed they could turn unresponsive cancers into responsive ones, thwarting tumor growth.

"One of the mechanisms for how this works is when you give an mRNA vaccine, that acts as a flare that starts moving all of these immune cells from bad areas like the tumor to good areas like the lymph nodes," Sayour said.

The next step is to launch a large clinical trial through the UF-led OneFlorida+ Clinical Research Network, a consortium of hospitals, health centers and clinics in Florida, Alabama, Georgia, Arkansas, California and Minnesota.

"One of our key motivations at OneFlorida is to move discoveries from academic settings out into the real world and the places where patients get care," said Betsy Shenkman, Ph.D., who leads the consortium.

If confirmed, the new findings unlock numerous possibilities, and the researchers said an even better nonspecific universal vaccine could be designed. For patients with advanced cancers, the increased survival from such a universal vaccine could provide a priceless benefit: more time.

"If this can double what we're achieving currently, or even incrementally -- 5%, 10% -- that means a lot to those patients, especially if this can be leveraged across different cancers for different patients," said Sayour, an investigator with UF's McKnight Brain Institute.

The study was funded by the National Cancer Institute and multiple foundations.

Sayour, Grippin and Mitchell hold patents related to UF-developed mRNA vaccines that are licensed by iOncologi Inc., a biotech company born as a "spinout" from UF in which Mitchell holds interest.