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Order of Gene Mutation: Predicting What Cancer Will Do Next

December 30, 2021

Over the last decade, scientists have gained a much greater understanding of which genes acquire mutations in particular cancers. Now, new research is showing that the order in which the mutations are acquired could have a significant impact on the cancer's clinical features and response to therapy.

According to the findings from a recent study led by Christina A. Ortmann, MD, and David G. Kent, PhD, published in The New England Journal of Medicine, a cancer's path changes depending on the order of certain "driver mutations." Drs. Ortmann, Kent, and colleagues analyzed blood samples from 246 patients with myeloproliferative neoplasms (MPNs) and discovered that acquired mutations in the Janus kinase 2 (JAK2) or TET2 genes later determined the clinical features, response to target therapy, and clonal evolution of the disease.

"These findings are exciting because we were able to study the very early stages of cancer," Dr. Kent told ASH Clinical News. "We were able to show that the disease develops differently depending on which mutation comes first."

MPNs – which develop into leukemia in 5 to 10 percent of cases – lend themselves to this type of research because they reflect earlier stages of development that may not be accessible in other types of cancer. Scientists are also able to identify clonal populations that have enough cells for genotypic and phenotypic analysis, Dr. Kent pointed out.

One-tenth of the 246 patients had mutations in both the JAK2 and TET2 genes; mutation order was determined by genotyping hematopoietic colonies or using next-generation sequencing. Of these patients, there were 12 samples in which the TET2 mutated first, and 12 samples in which the JAK2 mutation came first.

Then, through analysis of the patient-derived clonal populations of stem and progenitor cells, the researchers were able to develop a model for the effects of mutation order on the biology of MPNs: When a TET2 mutation was acquired first, expansion of hematopoietic stem and progenitor cells was favored, but expansion of lineage-committed erythroid cells was blocked until acquisition of a JAK2 mutation. By contrast, in JAK2-first patients, there was an increase in the number of megakaryocytic and erythroid cells, but not expansion of hematopoietic stem and progenitor cells until acquisition of a TET2 mutation.

Mutation order also was associated with several clinical features:

  • Patients who acquired the TET2 mutation first were an average of 12.3 years older than those who acquired the JAK2 mutation first (mean age at diagnosis = 71.5 years vs. 59.2 years; p = 0.04)
  • JAK2-first mutation patients were more likely to present with polycythemia vera than essential thrombocytopenia (p = 0.05)
  • The disease was noticeable 10 years earlier in people with JAK2-first mutation (60.71 years vs. 71.17 years; p = 0.002)
  • Despite presenting at a younger age, JAK2-first mutation patients were more likely to have a thrombotic event (p = 0.02)

The cells of JAK2-first patients had a higher sensitivity to the anti-JAK2 drug ruxolitinib. However, this sensitivity did not necessarily translate into better response from that medication.

According to Dr. Kent, the results of the study demonstrate that "the order of mutation acquisition can impact disease pathogenesis. Patients with known mutations have distinct diseases depending on which mutation came first."

Knowing the mutation order of a patient with MPN could potentially guide physicians in treatment decisions – particularly in understanding the timing and presentation of thrombotic risk for patients with the JAK2-first mutation.

"An understanding of mutation order might improve the delivery of targeted therapy to attenuate early driver events that are present in the trunk of the evolutionary tree of the tumor," Charles Swanton, MD, PhD, wrote in an editorial accompanying the study by Drs. Ortmann and Kent. "That is, driver mutations that are present in all cells, influencing the behavior of the whole tumor early in evolution, would be targeted."


  • Ortmann C, Kent D, Nangalia J, et al. Effect of mutation order on myeloproliferative neoplasms. N Engl J Med. 2015;372:601-12.
  • Swanton C. Cancer evolution constrained by mutation order. N Engl J Med. 2014;372:661-3.


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