Researchers announced on June 18 that a genetic mutation commonly associated with a rare group of blood cancers does not always result in the development of the disease. The study provides new insight into the early phases of these conditions and may help inform more tailored monitoring strategies for patients.
Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are a set of blood cancers characterized by an overproduction of red blood cells, certain white blood cells, or platelets. Many cases are linked to a specific mutation in the JAK2 gene, known as JAK2V617F.
The research team analyzed data from nearly 20,000 participants in the Danish General Suburban Population Study, focusing on those living in Zealand, Denmark. They identified 67 individuals carrying the JAK2V617F mutation. "Specifically, we were able to get data on the participants' variant allele fraction, or VAF, over a 10-year period from a sample of the general public, not just patients," Snyder says.
Snyder explained that VAF represents how many copies of the mutated gene exist compared to normal copies within each cell: "Every cell that has DNA has two copies of JAK2, but not every copy has the same mutation status," Snyder continues. "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."
Using participant data and mathematical modeling developed at Roskilde University in Denmark—where Snyder was formerly an assistant professor—the researchers found varied outcomes for those with this genetic change. According to their model, in 70% of cases mutated cells likely outcompeted normal ones; in 18% mutants had a disadvantage; and in 12% there was no clear advantage or disadvantage between mutant and normal cells.
Of those carrying JAK2V617F, only thirty-seven later developed MPNs—a lower rate than previously expected based on earlier studies. "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 says. "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 said future research will examine other factors such as chronic inflammation.
