Published on March 11, 2021
Researchers Identify Timeline of JAK2 Gene in MPN Patients
Researchers at Harvard Medical School (HMS) and the Dana-Farber Cancer Institute have been able to calculate when the genetic mutation that caused a myeloproliferative neoplasm (MPN) first appeared in two patients with the disease.
In a 63-year-old patient, it occurred at around age 19; in a 34-year-old patient, at around age 9.
The findings, which were published last week in the journal Cell Stem Cell, add to a growing body of evidence that cancers slowly develop over long periods of time and could inform new approaches for early detection, prevention or intervention, HMS reported.
"For both of these patients, it was almost like they had a childhood disease that just took decades and decades to manifest, which was extremely surprising," co-corresponding study author Dr. Sahand Hormoz, an assistant professor of systems biology at HMS and Dana-Farber, told the medical school.
"I think our study compels us to ask, when does cancer begin, and when does being healthy stop? It increasingly appears that it's a continuum with no clear boundary, which then raises another question: When should we be looking for cancer?"
To calculate when the original cancer-causing mutation appeared, researchers collected bone marrow stem cells from the two patients. Like most MPN patients, their disease was driven by a mutation in the JAK2 gene. The team isolated a number of stem cells that contained the JAK2 mutation, as well as normal stem cells, from each patient and then sequenced the entire genome of each individual cell, the article explained.
Combined with calculations of the rate at which mutations accumulate, the team could estimate when the JAK2 mutation first occurred in the two patients, along with the number of cells that carried the mutation over time. This enabled them to reconstruct the history of disease progression.
"Initially, there's one cell that has the mutation. And for the next 10 years there's only something like 100 cancer cells," Dr. Hormoz told HMS. "But over time, the number grows exponentially and becomes thousands and thousands. We've had the notion that cancer takes a very long time to become an overt disease, but no one has shown this so explicitly until now."
The team also found that the JAK2 mutation “conferred a certain fitness advantage” that helped cancer cells outcompete normal bone marrow stem cells over long periods of time. This could explain why the disease progresses faster in some individuals than others, such as the 34-year-old MPN patient, HMS reported.
What About Other Cancers?
The approach is generalizable to other types of cancer, according to Dr. Hormoz. However, MPNs are driven by a single mutation in a very slow-growing type of stem cell. Other cancers may be driven by multiple mutations, or in faster-growing cell types, and further studies are needed to better understand the differences in evolutionary history between cancers, HMS said.
Dr. Hormoz’s team is currently working on developing early detection technologies, reconstructing the histories of greater numbers of cancer cells, and investigating why some patients’ mutations never progress into full-blown cancer, but others do.
"To me, the most exciting thing is thinking about at what point can we detect these cancers," Dr. Hormoz said. "If patients are walking into the clinic 40 years after their mutation first developed, could we have caught it earlier? And could we prevent the development of cancer before a patient ever knows they have it, which would be the ultimate dream?"
- Reconstructing the Lineage Histories and Differentiation Trajectories of Individual Cancer Cells in Myeloproliferative Neoplasms. Cell Stem Cell. March 2021.
- When Does a Cancer First Arise? Harvard Medical School. March 2021.
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