New and old cell mutations interact to shape cancer risk
- New research reveals that newly acquired cell mutations interact with inherited mutations to shape cancer risk, particularly for blood cancers like acute myeloid leukemia (AML).
- The study found that individuals with clonal hematopoiesis, a condition where mutated stem cells multiply and increase the risk of blood cancer, are more likely to develop AML if they have inherited mutations in certain genes.
- Researchers discovered that inherited mutations can influence patterns of newly acquired mutations that cause clonal hematopoiesis, increasing the risk of transforming into leukemia.
- The study suggests that detecting and measuring both inherited cancer risk and clonal hematopoiesis could help identify individuals who would benefit from early prevention strategies, such as targeted therapies for high-risk mutations.
- Future research aims to develop new blood tests to detect individuals with clonal hematopoiesis before they show symptoms, using genetic data from large-scale genomic studies like the UK Biobank Resource and the All of Us Research Program.
A new study shows that newly acquired cell mutations interact with inherited mutations—those passed down by your parents—in important ways that influence your lifetime cancer risk.
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.
Understanding the interactions between inherited and acquired mutations could guide development of new methods for early detection and prevention of cancer.
The research in Nature Genetics focused specifically on the risk of blood cancers such as acute myeloid leukemia (AML), although interactions between inherited and acquired mutations likely have roles in other types of cancer.
Inherited mutations are carried in the egg and sperm and are therefore present in every cell starting at birth, whereas acquired mutations accumulate gradually with age in different cells. Led by Kelly Bolton, an assistant professor of medicine in the Division of Oncology at Washington University School of Medicine in St. Louis and the study’s senior author, the research team set out to understand how interactions between these two types of mutations influence a person’s risk of developing blood cancer.
In particular, they focused on a blood condition called clonal hematopoiesis that is known to increase a person’s risk of developing blood cancer. Clonal hematopoiesis is caused by a mutation in blood stem cells—cells that give rise to all the different cell types in the blood—that gives those cells a slight survival advantage over the normal stem cells. Such stem cell clones multiply more and are at risk of transforming to blood cancer.
“Most people with clonal hematopoiesis never develop blood cancer,” says Bolton, who treats patients at Siteman Cancer Center, based 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.”
Studying genomic data of more than 730,000 people, including from blood samples, the researchers found that clonal hematopoiesis was more common among those with inherited mutations in certain genes already known to increase the risk of cancer.
They also found that such inherited mutations had an impact on patterns of newly acquired mutations that cause clonal hematopoiesis. If stem cell clones go on to acquire just a handful more harmful mutations, the clonal hematopoiesis can transform into a blood cancer, such as AML, in which the cells stop doing their jobs and multiply until they crowd out healthy cells.
With the goal of finding ways to detect and eliminate pre-cancerous cells in people at high risk of blood cancer, Bolton and her colleagues found that among individuals with clonal hematopoiesis, those who had inherited mutations that predispose to clonal hematopoiesis had a higher risk of developing blood cancer than those without inherited mutations.
“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 says.
“The goal is to stamp out the weeds early, before they can take root and become full-blown cancer.”
Though clonal hematopoiesis is part of normal aging, certain factors such as smoking or prior exposure to radiation or chemotherapy can speed up the process and increase the risk of it transforming into cancer. Still, some people progress to cancer without major environmental risk factors, and the new study suggests that the interaction of their inherited genome with newly acquired mutations plays an important role in this cancer progression.
The study’s first author, Jie Liu, a graduate student in Bolton’s lab, notes: “It’s exciting to see how combining large-scale genomic data can reveal how inherited and acquired mutations work together to influence cancer risk. 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.”
Bolton says being able to detect and measure both inherited cancer risk and clonal hematopoiesis would likely be a powerful way to identify individuals who would benefit most from early prevention strategies, such as targeted therapies for the most damaging mutations.
At present, clonal hematopoiesis is difficult to identify without specialized blood tests that are not given as part of routine care. Even though such individuals already have clones taking up a greater proportion of their blood stem cells, they can still show normal blood cell counts as part of blood tests typically given at an annual well visit, for example.
In theory, if scientists know what gene mutations to look for, they could develop new blood tests to identify such individuals before any evidence of a problem could be detected with routine blood screening tests. The new study singles out many genes of interest that could be key in the future development of such a blood test.
“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 says.
“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.”
Researchers at Siteman are now conducting clinical trials investigating whether specific drugs called IDH1 and IDH2 inhibitors can stop the expansion of certain types of blood stem cell clones before they become cancer. For now, such trials only include people who could be identified as having clonal hematopoiesis because they already had progressed to having abnormal blood cell counts, placing them on the cusp of full-blown leukemia.
“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 says.
“There are a lot of targeted therapies that are being developed right now and new approaches researchers are looking at for this purpose.”
Support for this work came from the National Institutes of Health (NIH), the MDS Foundation, the Children’s Discovery Institute, a Prostate Cancer Foundation Challenge Award, the Edward P. Evans Foundation, the SciLifeLab & Wallenberg Data Driven Life Science Program, the Swedish Cancer Foundation, the Swedish Research Council, a Burroughs Wellcome Fund Career Award for Medical Scientists, a Pew Charitable Trusts and Alexander and Margaret Steward Trush Pew-Stewart Scholar for Cancer Research Award, and a Hevolution/AFAR New Investigator Award in Aging Biology and Geroscience Research.
The study was conducted using the UK Biobank Resource and data provided by patients and collected by the National Health Service. It was also conducted using data from the All of Us Research Program of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Source: Washington University in St. Louis
The post New and old cell mutations interact to shape cancer risk appeared first on Futurity.