Mutation Order Affects Cancer Behavior

The chronologic sequence in which a patient's genes are mutated can affect the biology of the tumor and clinical features of the disease, according to a study published in The New England Journal of Medicine. Mutation order also seems to influence how cancer cells respond to a drug, suggesting that physicians may need to take this factor into account when devising treatment plans for patients.

“We are spending a lot of time understanding what genes are mutated in various tumors,” says senior author Tony Green, MD, PhD, a professor of hemato-oncology and head of the hematology department at the University of Cambridge, UK. Whether the order in which these mutations occur matters “is an absolutely fundamental question that was unanswered” until now, he says.

Green's team studied patients with myeloproliferative neoplasms, about one tenth of whom have mutations in both the TET2 and JAK2 genes. By isolating stem and progenitor cells from the peripheral blood of 24 patients and genotyping hematopoietic colonies, the team could determine whether the patients acquired a TET2 or JAK2 mutation first.

In JAK2-first patients, the JAK2 mutation increased proliferation of stem and progenitor cells. However, a JAK2 mutation did not have the same effect in patients who acquired a TET2 mutation first. Furthermore, a JAK2 mutation triggered upregulation of genes involved in proliferation only if the patient did not already have a TET2 mutation.

When the researchers studied an expanded group of 48 patients, they found that JAK2-first patients showed abnormal blood counts about 10 years earlier, on average, than TET2-first patients. The JAK2-first patients also were more likely to have polycythemia vera, a condition in which red blood cells are overproduced, and blood clots. In addition, cells from these patients were more sensitive to ruxolitinib (Jakafi; Incyte), a JAK2 inhibitor.

“It's a dramatic example of the order of mutations determining the phenotype,” says Alan Ashworth, PhD, president of the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, who was not involved in the study. The results suggest that the effectiveness of treatments will vary depending on mutation order, he says, and “you need to think about the order and then use the therapies appropriately.”

Green hopes the work will encourage researchers to study the same question in other types of cancer. Because genetic interactions are critical for development of solid tumors, “it's probably true that the order of mutation also matters here,” says Ashworth. “I'm convinced that this will be a more general phenomenon.”