Genetic mutations linked to myeloproliferative neoplasms emerge in childhood or even in utero, decades before they cause cancer, according to a late-breaking abstract presented at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition.1
“Our preliminary findings show these cancer driver mutations were often acquired in childhood, many decades before the cancer diagnosis,” said senior investigator Jyoti Nangalia, MBBChir, of the Wellcome Sanger Institute and University of Cambridge in the United Kingdom. “Our results finally answer the common question posed by patients, ‘How long has this cancer been growing?’ as we were able to study how these particular cancers developed over the entire lifetime of individual patients.”
“Our preliminary findings show these cancer driver mutations were often acquired in childhood, many decades before the cancer diagnosis.”— Jyoti Nangalia, MBBChir
Tweet this quote
Philadelphia chromosome–negative myeloproliferative neoplasms (primarily encompassing polycythemia vera, essential thrombocytopenia, and myelofibrosis) are unique cancers capturing the earliest stages of tumorigenesis through disease evolution. Most patients harbor JAK2 V617F mutations, which may be the only driver mutation or can occur in combination with others in genes such as DNMT3A or TET2.
Whole-Genome Sequencing and More
In the study, researchers traced the genetic origins of Philadelphia chromosome–negative myeloproliferative neoplasms. They performed whole-genome sequencing of 952 individual single-cell–derived hematopoietic colonies, then conducted targeted resequencing of longitudinal blood samples from 10 patients diagnosed with the disease between the ages of 20 and 75 years. They identified 448,553 somatic mutations and used them to construct phylogenetic trees of hematopoiesis, tracing blood cell lineages back to embryogenesis. They also timed the acquisition of driver mutations, characterized the dynamics of tumor evolution, and measured clonal expansion rates over the lifetime of patients.
“For the 10 patients with a variety of phenotypes, we took peripheral blood or bone marrow samples and grew out single-cell–derived hematopoietic colonies. Each colony underwent whole-genome sequencing, and each whole genome of the colony reflected that of the single cell from which the colony was derived,” she explained. “As cells are dividing, mutations are being acquired and passed down over time. Mutations within individual cells represent natural bar codes that can be used to trace back the ancestry of cells to the start of life.”
Stem cells acquire roughly 18 mutations across an individual’s genome per year. By applying the patient-specific mutation rate and clonal-specific rates, they could put “start and end times” to each individual branch across a patient’s phylogenetic tree, she said. In the 10 patients studied, the first cancer-linked mutations emerged as early as a few weeks after the start of life and up to the first decade of childhood, despite clinical disease presenting many decades later in life.
“In fact, in one patient, the JAK2 mutation was acquired more than 50 years before their diagnosis…. We were not expecting this,” Dr. Nangalia said.
Clonal Growth Rate Determined Latency to Diagnosis
Of note, the rate of clonal growth determined the latency to the diagnosis of the patients’ cancer, and this varied greatly. Patients with a very slow growth rate took about 50 years to present with disease, whereas those with faster growth rates presented by 10 years or so, she continued.
“In one patient, multiple different clones were acquired very early in life. One clone was growing at a rate of 10% per year, whereas another grew at 200% per year, doubling every 7 months in size,” she said.
KEY POINTS
- Through whole-genome sequencing, researchers have traced the genetic origins of myeloproliferative neoplasms to early childhood, and even to conception.
- They identified 448,553 somatic mutations and used them to construct phylogenetic trees of hematopoiesis.
- Whole-genome sequencing of 952 individual single-cell–derived hematopoietic colonies produced profiles that were then applied in targeted resequencing of longitudinal blood samples from 10 patients diagnosed with these diseases as young as
age 20. - They were able to estimate the time at which each patient acquired JAK2 V617F and other driver mutations and to determine clonal expansion rates.
Dr. Nangalia said she now wants to examine a healthy population for the prevalence of these mutations, “not only detecting them but understanding in which people they grow,” she said. “Finding the mutation is only half the show.”
The researchers would also like to look for genetic ancestry in other myeloid malignancies. “Understanding the timelines of development of different cancers is critical for efforts aimed at early cancer detection and prevention,” she said.
DISCLOSURE: Dr. Nangalia reported no conflicts of interest.
REFERENCE
1. Williams N, Lee J, Moore L, et al: Driver mutation acquisition in utero and childhood followed by lifelong clonal evolution underlie myeloproliferative neoplasms. 2020 ASH Annual Meeting & Exposition. Abstract LBA-1. Presented December 8, 2020.
