Blood Cancer's Genetic Warning Signs May Appear Years Before Diagnosis, Landmark Study Reveals
核心洞察
Researchers at the Wellcome Sanger Institute (搜索) combined whole-genome sequencing with decades of clinical data to trace how myeloproliferative neoplasms (搜索) (MPNs) evolve over time.
Patients with stable disease showed genetically "steady" blood cell populations, while those who progressed acquired new DNA mutations detectable years before clinical deterioration.
Some patients lacking JAK2 (搜索), CALR (搜索), or MPL (搜索) mutations showed genomic patterns consistent with normal aging rather than cancer, challenging current diagnostic assumptions.
Two complementary studies are reshaping the understanding of how chronic blood cancers develop, revealing that genetic warning signs can appear years before clinical diagnosis and that cancer-driving mutations do not always result in disease.
The research, published in Cancer Discovery and Proceedings of the National Academy of Sciences respectively, provides new insight into the earliest phases of myeloproliferative neoplasms (搜索) (MPNs)—a group of rare, long-lasting blood cancers that cause the overproduction of red blood cells, certain white blood cells, or platelets.
Tracking Cancer Evolution Over Decades
A team led by the Wellcome Sanger Institute (搜索) and collaborators at Cambridge University Hospitals NHS Foundation Trust followed 30 patients with chronic blood cancers, primarily MPNs, combining whole-genome sequencing with extensive clinical information including nearly 8,000 blood test results, treatment records, and disease data. More than 450 samples were examined through repeated genomic testing, with some patients monitored through routine clinical care for as long as 25 years.
Using DNA taken from blood cells, the researchers created genetic "family trees" that allowed them to trace the origins of cancer clones—groups of genetically identical cells that later contributed to disease progression. The analysis revealed distinct evolutionary patterns.
"By reconstructing the ancestry of cells, we were able to see different evolutionary patterns between patients who had stable disease compared to others who progressed," said Dr. Daniel Leongamornlert, first author at the Wellcome Sanger Institute (搜索).
People whose disease remained clinically stable tended to have genetically "steady" blood cell populations that acquired few or no additional mutations. By contrast, patients whose disease progressed developed new DNA changes over time. The results suggest that progression in chronic blood cancers may be biologically "encoded" years before a patient's condition visibly deteriorates.
Challenging Diagnostic Assumptions
The Sanger-led team also examined patients who lacked mutations in the three genes most commonly associated with MPNs: JAK2 (搜索), CALR (搜索), or MPL (搜索). Around 10 percent of MPN patients do not carry any of these common genetic changes, and doctors may diagnose cancer largely by examining the appearance of cells in the bone marrow.
When researchers reconstructed "family trees" from around 200 blood cell genomes belonging to these patients, they observed changes more consistent with normal aging rather than patterns typical of cancer. This finding challenges the assumption that everyone with certain unusual bone marrow features has a true blood cancer.
The results support new British Society for Haematology guidelines recommending that some patients initially be described as having "thrombocytosis without JAK2 (搜索), CALR (搜索) or MPL (搜索) mutations"—meaning a high platelet count without clear genetic evidence of cancer—rather than being immediately diagnosed with a blood cancer.
The JAK2 (搜索) Mutation Is Not Destiny
In a separate study, researchers from North Carolina State University, Roskilde University, and Zealand University Hospital analyzed data from the Danish General Suburban Population Study, which contained blood samples and health questionnaires from nearly 20,000 residents of Zealand, Denmark.
The group identified 67 people carrying the JAK2V617F mutation—a genetic change known to drive many MPN cases—and tracked their variant allele fraction (VAF) over a 10-year period. VAF represents the number of mutated copies of the gene versus normal copies.
"Most of the work around this mutation is looking at the VAF of patients with cancer. But to figure out how the disease progresses from a healthy state, we need to look at VAF before cancer develops," said Jordan Snyder, assistant teaching professor of mathematics at North Carolina State University and corresponding author of the study.
The research team created a stochastic mathematical model describing how the mutation might proliferate in blood stem cells. According to the model, in 70% of cases the mutated cells were likely to outcompete their normal counterparts; in 18% of cases mutants had a competitive disadvantage; and 12% showed neither an advantage nor a disadvantage.
Critically, only 37 of the 67 people with the JAK2V617F mutation were later diagnosed with an MPN blood cancer—fewer than might be expected based on previous research.
"While the exact mechanism of action from this mutation is not completely understood, the previous assumption was that the mutation would always eventually out-compete healthy copies, leading to cancer," Snyder said. "But these data point to the idea that there is more to it. It's not just the presence of the mutated gene—something is happening to help that mutated copy out-compete the normal ones."
Snyder indicated that next steps will involve examining potential contributing factors such as chronic inflammation.
Toward Genomic Monitoring in Routine Care
Together, the findings highlight the potential clinical benefits of using genomic information more routinely in cancer care. Genetic testing could help doctors distinguish stable disease from cancers likely to progress, refine uncertain diagnoses, and guide more precise treatment strategies.
Dr. Jyoti Nangalia, senior author at the Wellcome Sanger Institute (搜索) and Honorary Consultant Haematologist at Cambridge University Hospitals NHS Foundation Trust, noted: "These are patients we have cared for and followed in our clinic for over 15 years. It can be incredibly difficult to predict how their cancers might change over time. By combining long-term clinical care with regular genomic analysis, we've been able to watch how the genetic code of their disease evolves in advance of clinical changes."
Dr. Dani Skirrow, Research Information Manager at Cancer Research UK, which part-funded the Sanger study, added: "We're in a golden age of research where advances in technology mean we can rapidly read DNA to find the errors in the code that can lead to cancer. This type of discovery research is essential to improve how we monitor people at risk of blood cancer, and to help us find better ways to prevent, detect and treat the disease so people can live longer, better lives."
Around 40,000 people in the UK are living with MPNs, with approximately 4,000 new cases diagnosed each year. The Sanger study was supported in part by Wellcome and Cancer Research UK, while the Danish population study was supported by the Lundbeck Foundation Fellowship under grant R335-2019-2300.