As we age, our cells replicate, and the DNA in these cells can acquire mistakes — or mutations — every time the sequence is copied. Most newly acquired mutations are harmless, but some can tip the balance toward cancer development later in life.

A new study led by WashU Medicine researchers shows that these newly acquired mutations interact with inherited mutations passed down by our parents in ways that influence a person’s lifetime cancer risk. Understanding these interactions could inform new ways to fight and prevent cancer, sooner.

This work signals a fundamental shift in the fight against blood cancer, exemplifying how WashU Medicine decodes disease to move medicine from difficult treatment to proactive prevention.

The research team, led by Kelly Bolton, MD, PhD, an assistant professor of medicine in the Division of Oncology at WashU Medicine and the study’s senior author, focused on a common age-related blood condition called clonal hematopoiesis. This condition arises when a blood stem cell — the source of all blood cells — acquires a mutation that gives it a growth advantage over normal stem cells.

“Most people with clonal hematopoiesis never develop blood cancer,” said Bolton, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and WashU Medicine. “To a certain extent, it’s a normal aging process. However, we think that many if not all individuals who develop blood cancer pass through a phase of clonal hematopoiesis at some point. We are still in the early stages of trying to figure out which individuals with clonal hematopoiesis will go on to develop blood cancer and which will not.”

By analyzing genomic data from more than 730,000 people, the team made two key discoveries. First, clonal hematopoiesis was more common in people who had inherited certain cancer-risk genes. Second, these inherited genes influenced the type of new mutations that arose. This interaction is critical — if a growing clone of stem cells picks up just a few more harmful mutations, it can transform into a blood cancer like AML.

“Our study is a first look at the inherited genetic background that is providing the soil, so to speak, and we’re seeing what undesirable seeds that are acquired later in life are more or less likely to grow from that soil,” Bolton said. “The goal is to stamp out the weeds early, before they can take root and become full-blown cancer.”

This discovery explains why some people develop cancer even without major environmental risks — their underlying genetics play a decisive role.

“It’s exciting to see how combining large-scale genomic data can reveal how inherited and acquired mutations work together to influence cancer risk,” said Jie Liu, the study’s first author and a graduate student in Bolton’s lab. “These insights move us closer to identifying high-risk individuals before cancer develops. Our work shows that it’s not just the mutations you’re born with or those you acquire later in life, it’s the interaction between them, and we can now measure that.”

Earlier intervention

Identifying people at highest risk could pave the way for powerful prevention strategies. Currently, clonal hematopoiesis is difficult to detect without specialized blood tests, as individuals can still show normal blood counts on routine panels — even while abnormal clones are expanding. The new study points toward a solution: by knowing which inherited and acquired mutations to target, scientists could develop new tests to find high-risk individuals long before routine screenings flag a problem. The research singles out numerous genes of interest for precisely this purpose.

“Because leukemia is so hard to treat, we hope to find ways to intervene early — when it’s still pre-cancerous — so we can stop clonal hematopoiesis from transforming into leukemia,” Bolton said. “We would want to start with preventive clinical trials for people who have certain inherited mutations and who already have evidence of clonal hematopoiesis, such as one or two clones expanding in their blood.”

This work is already informing clinical strategy. At Siteman, researchers are conducting trials to see if targeted drugs called IDH1/IDH2 inhibitors can stop the expansion of specific high-risk clones before they become cancer. Currently, these trials are limited to people whose clonal hematopoiesis has progressed enough to cause abnormal blood counts.

“We are hopeful about the prospects of these preventive treatments, but we would like to have tools to identify these individuals even earlier, before their blood cell counts become abnormal,” Bolton said. “There are a lot of targeted therapies that are being developed right now and new approaches researchers are looking at for this purpose.”