| The following article features coverage from the American Society of Hematology 2020 meeting. Click here to read more of Hematology Advisor‘s conference coverage. |
Myeloproliferative neoplasms (MPNs) were found to originate from driver mutations that occurred early in life, sometimes decades before clinical presentation, MPN diagnosis, and even before birth, according to study findings presented at the virtual 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.
“Recurrent mutations in cancer-associated genes drive [tumor] growth, however, the timing of driving mutations and the dynamics of clonal expansion remain largely unknown,” the authors wrote.
A team of UK-based researchers set out to determine the timing of driver mutations and clonal dynamics in adults with MPNs. They conducting whole-genome sequencing of individual single cell-derived hematopoietic colonies (n=952) with targeted resequencing of longitudinal blood samples from 10 patients aged 20 to 76 years who presented with Philadelphia-negative MPNs.
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The team used somatic mutations (n=448,553), which accumulate over time, to reconstruct phylogenetic trees of hematopoiesis to trace blood cell lineages back to embryogenesis. By characterizing the dynamics of tumor evolution and measuring clonal expansion rates over patient lifetime, the investigators were able to estimate the timing of driver mutations.
In patients with JAK2V617F as their first or only driver mutation, the mutation was acquired in utero or during childhood in all patients, ranging from a few weeks postconception to 11.4 years of age. Notably, the ages of MPN presentation varied amongst these patients. The mean latency between JAK2V617F mutation and clinical presentation was 34 years (range, 20-54). Regardless of the first driver mutation, subsequent driver mutations happened decades later. In addition, disease latency showed a similarly broad range of 12 to 27 years if JAK2V617F was a second driver mutation.
DNMT3A mutations occurred as the first driver event, subsequent to JAK2 mutation, or as independent clonal hematopoiesis clones in patients. Similarly, DNMT3A mutations were also traced back to an in utero or childhood origin, ranging from 1.2 weeks postconception to 7.8 years of age.
The investigators also noted that similar genetic changes repeatedly occurred in unrelated clones within the same patient with MPN. This “parallel evolution” was reported for chr9p loss of heterozygosity (9pUPD), chr1q+, and mutations in the genes known to drive myeloid cancers.
The team also estimated that normal hematopoietic stem cells accumulated approximately 18 somatic mutations per year; whereas, mutant clones, particularly those with JAK2 mutations, acquired 1.5 to 5.5 excess mutations per year, and had shorter telomeres, indicating an increased number of cell divisions.
The investigators also modeled the rates of clonal expansion, which were found to vary substantially across patients, and within individual patients. For example, a patient with an in utero acquired DNMT3A mutation, clonal expansion was measured at less than 10% a year, and took 30 years to reach 1% clonal fraction, while a clone with mutations in JAK2, DNMT3A and TET2 had a clonal expansion of more than 200% per year. Aside from driver mutations, other factors that could affect variation in clonal expansion among individuals include germline, cytokine, or stem cell differences.
Rates of JAK2-mutant clonal expansion were more predictive of time to clinical presentation than patient age at mutation acquisition and tumor burden at diagnosis, suggesting these mutant clones determine if and when clinical manifestations occur.
Depending on the sensitivity of the test, these clones could be detected in blood decades before clinical presentation, which would allow physicians to minimize thrombotic risk and target mutant clones in at-risk individuals.
“Early detection of mutant-JAK2 together with determination of clonal expansion rates could provide opportunities for early interventions aimed at [minimizing] thrombotic risk and targeting the mutant clone in at risk individuals,” the investigators concluded.
Read more of Hematology Advisor’s coverage of the ASH 2020 meeting by visiting the conference page.
Reference
Williams N, Lee J, Moore L, et al. Driver mutation acquisition in utero and childhood followed by lifelong clonal evolution underlie myeloproliferative neoplasms. Presented at: American Society of Hematology (ASH) 62nd Annual Meeting and Exposition; December 5-8, 2020. Abstract LBA-1.
