Rare Gene Mutations Linked to Risk Across Multiple Cancer Types

Most people who learn they carry a mutation in the BRCA2 gene think of it as a breast and ovarian cancer gene. Angelina Jolie’s 2013 public disclosure of her own BRCA mutation and her decision to undergo a preventive mastectomy increased public awareness, but it also fixed the gene in the popular imagination as a women’s health issue. A new study in Human Genetics and Genomics Advances led by Dr. Austin Hammermeister Suger, who completed his PhD in epidemiology at the University of Washington in March 2026, suggests this framing is too narrow. The same is true for dozens of other genes that shape cancer risk. These findings have potential implications for how doctors counsel patients who carry hereditary cancer mutations and for the millions of people who may not realize their known genetic risk extends beyond a single cancer type. 

The study, conducted with colleagues at the Fred Hutch Cancer Center and drawing on data from more than 729,000 participants across the United States and United Kingdom, examined whether rare mutations in specific genes raise a person’s risk not just for one cancer, but for many different cancers simultaneously. The answer, it turns out, is yes. 

The phenomenon at the center of the study is called pleiotropy: the property of a single gene having functional effects across multiple diseases or conditions. “A lot of the time, people think about one gene being linked to a specific disease,” Hammermeister Suger says. “But really, what the genes are linked to are very specific roles in your body—what we call biological processes—and a disruption in that biological process could result in two different conditions that are somewhat similar, or even two completely distinct conditions.” In cancer, the biological processes most often implicated are the ones that govern how cells repair DNA damage and ones that regulate how quickly they divide. When those systems break down, the consequences can be seen across many different tissues and tumor types. 

The researchers identified 33 genes where a rare, damaging mutation is associated with elevated risk for multiple cancers at once. BRCA2, far from being limited to breast and ovarian cancer, showed significant associations with all six of the broad cancer categories in the study. The CHEK2 gene, which most people in the medical community know primarily as a breast cancer risk gene, was linked to 14 different cancer types in this study, including prostate, kidney, thyroid, and leukemia. These findings push against a long held tendency to think about cancer in silos, and suggest that the underlying biology is more interconnected.  

None of this would have been visible without a dataset of unusual size. The study combined participants from the UK Biobank and the All of Us Research Program in the United States, two of the largest biomedical databases in the world. Hammermeister Suger says the scale was not incidental to the findings, particularly when looking for rare mutations.  “A particular mutation might be carried by maybe 10 to 20 people on the entire planet,” he says. “In order to even catch one of those mutations occurring, you need enormous sample sizes.” Of the roughly 8 million genetic mutations analyzed in the study, over 80% were observed in 10 or fewer people 

The size of the dataset also made it possible to include cancers that don’t have enough diagnosed cases for a typical population study. Typically, due to a lack of information and funding, these types of cancers rarely appear in genetic studies at all. But by looking across cancer types simultaneously and grouping them by shared biological features, the researchers were able to include more rare cancers in the analysis, potentially surfacing risk factors that would otherwise go unstudied. 

Perhaps the most unexpected finding involved a gene called RTEL1, which plays a role in building and maintaining the protective caps at the ends of chromosomes, known as telomeres. Rather than raising cancer risk, certain mutations in RTEL1 were associated with reduced risk for up to nine different cancers. “That was probably the most interesting finding across the whole study,” Hammermeister Suger says. “It’s a very complicated relationship with both cancer and actually a lot of other diseases associated with aging.” A different class of mutations in the same gene, however, was associated with increased risk for lung and skin cancer, showing how a single gene can have different effects on disease risk depending on the mutation. 

For people outside the research community, the study’s most immediate relevance may be in how it changes the conversation around hereditary cancer risk. Right now, genetic testing guidelines tend to focus narrowly: a BRCA mutation prompts screening for breast and ovarian cancer; a CHEK2 mutation prompts attention to breast cancer. What this study suggests is that those guidelines may eventually need to expand. “If you’re coming from a family with a particular hereditary cancer risk,” Hammermeister Suger says, “just be aware. Maybe have that conversation. There are these core biological processes involved in cancer, if you’re coming from that background, it’s possible you also have not quite as extreme, but at least a slight, increase in risk for some other cancers.” 

However, it’s important not to overstate what the research currently means for clinical practice. Translating findings from a population study into actionable guidance for individual patients takes time, replication, and a level of clinical validation that this study alone cannot provide. But he hopes the work nudges people toward a more nuanced understanding of what genetic risk actually means. Cancer risk is not a binary verdict. “My hope for the population,” he says, “is just to think a little bit more like: I might have this increased genetic risk for cancer, but that doesn’t necessarily mean there’s nothing I can do about it. It doesn’t necessarily mean that I’m going to get cancer. It could just be an indication that this one piece of my risk factor pie for cancer is slightly larger.” 
 
In July 2026, the National Cancer Institute awarded a new five-year R01 grant that includes UW Epidemiology professor Sara Lindström, who worked with Hammermeister Suger, as a co-investigator. The grant will fund research through 2031 that pushes this work further. 

Readers in the United States who want to contribute to this line of research can join the All of Us Research Program, which continues to recruit participants and accepts enrollment through its website and select retail health clinics.