The prostate is the single organ most frequently afflicted by cancer in men. Prostate cancer affects approximately 4 million American men, with another 330,000 men expected to be diagnosed with the condition this year alone.
Most prostate cancers arise late in life. The tumors grow slowly and remain in the prostate. However, there are several hundred thousand cases in which the cancer is more aggressive and grows quickly, spreading beyond the prostate into lymph nodes and bone.
Understanding why some prostate cancers grow slowly while others metastasize and become lethal is the central clinical question of prostate cancer management. If researchers could decipher the underlying pathology and predict a tumor's course of behavior, clinicians could avoid over-treating many patients while focusing on improving treatment for those with the most aggressive cases.
Paul C. Boutros, PhD, MBA, is a professor and director of the National Cancer Institute-designated cancer center at Sanford Burnham Prebys Medical Discovery Institute. In previous research, he and colleagues had discovered that permanent changes in prostate cancer DNA, called somatic mutations, shape the aggressiveness of cancers.
But this discovery led to a major new question: How do changes in the DNA lead to changes in the cancers that affect growth rates and response to therapy?
In a new paper, published June 17, 2026 in the journal Cancer Discovery, senior author Boutros and an international team of co-authors, identify the answer: prostate tumor methylation.
Methylation is a fundamental process in cell biology that involves chemical tags called methyl groups being attached to specific DNA segments. The process turns certain genes on or off. In cancer, methylation can reveal how a tumor is likely to behave or respond to treatments. Because methylation changes happen to DNA after mutations occur, it serves as the key link between cancer genetics and patient outcome.
To fully define this process, Boutros and colleagues created a compendium of 3,001 multi-ancestry prostate methylomes (a complete set of DNA methylation modifications) spanning normal tissue through localized prostate disease of all grades to advanced metastatic disease. A subset of 884 samples also had multi-omic DNA and/or RNA characterization. Samples for this study came from around the world.
Boutros' team found that of the millions of potential methylation patterns in prostate cancer, four specific patterns were extremely common. These so-called "methylation subtypes" recurred across patients and closely reflected the clinical aggressiveness of cancers. One subtype was associated with normal aging prostate and extremely slow growing cancers. Two subtypes were associated with prostate cancers that tended to grow at a moderate pace, but rarely moved out of the prostate. And the final subtype almost exclusively occurred in prostate cancers that metastasized and became lethal.
Not only did methylation patterns replicate in thousands of patients, said Boutros, but they also exhibited highly predictable patterns across age, ancestry and even the specific DNA mutations that occurred in each patient's cancer.
"Methylation was the way the cancer took the information from cancer genetics, patient lifestyle and other features and created a single signal that we could read," said Boutros. "That made it an ideal biomarker, and helped us learn what really makes prostate cancers so common, and so dangerous."
Takafumi Yamaguchi, a bioinformatician at Sanford Burnham Prebys and co-lead author of the study, noted the multidisciplinary collaboration underlying the research.
"A study like this is a beautiful, complex dance. There were 22 separate institutions from around the world working together. We needed to find ways for cancer biologists and statisticians to talk with urologists, radiation oncologists and pathologists. Many of the technologies, and the AI and data science techniques we used, didn't exist just 10 years ago, so there was a lot of learning for everyone!"
"Every research study leads to new questions," said Boutros, discussing next steps. "First and most importantly, we now want to work out how to get this information into prostate cancer clinics to help patients and their caregivers get the best possible treatment.
"Secondly, several parts of this study hint that oxygen flow in the prostate may be very important. We are going to test whether light exercise and similar strategies can help reduce the incidence of aggressive prostate cancer in clinical trials."
Additional authors include:
- Jaron Arbet at Beckman Research Institute of City of Hope
- Takafumi N. Yamaguchi, Rupert Hugh-White at Sanford Burnham Prebys
- Adriana Wiggins, Jieun Oh, Nicole Zeltser, Tsumugi Gebo, Rachel M.A. Dang, Raag Agrawal, Julie Livingstone, Adriana Salcedo, Amar U. Kishan at University of California, Los Angeles
- Yu-Jia Shiah, Adrien Foucal, Robert Lesurf, Cindy Q. Yao, Shadrielle Melijah G. Espiritu, Kathleen Houlahan, Fouad Yousif, Lawrence E. Heisler, Michael Fraser at Ontario Institute for Cancer Research, Canada
- Chol-Hee Jung, Bernard J. Pope, Niall M. Corcoran, Christopher M. Hovens at University of Melbourne, Australia
- Anthony T. Papenfuss at Walter and Eliza Hall Institute of Medical Research, Australia
- Alejandro Berlin, Theodorus van der Kwast at Princess Margaret Cancer Centre, Canada
- Melvin L.K. Chua at National Cancer Centre Singapore, Singapore
- Robert G. Bristow at Manchester Cancer Research Center, UK
This study was supported by Movember funds through Prostate Cancer Canada and with the additional support of the Ontario Institute for Cancer Research, funded by the Government of Ontario. Additional support through a Terry Fox Research Institute New Investigator Award and a CIHR New Investigator Award, the Canadian Cancer Society, a Canadian Cancer Society Research Scientist Award, a Cancer Research UK core investigator grant, the Canadian Epigenetics, Environment and Health Research Consortium, the National Institutes of Health, National Institute of General Medical Sciences, a Prostate Cancer Foundation Special Challenge Award, the Department of Defense and the UCLA Jonsson Comprehensive Cancer Center Fellowship.
The study's DOI is 10.1158/2159-8290.CD-25-0761
