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ASH 2020: Early Signs of Risk for Myeloproliferative Neoplasms May Appear in Childhood or in Utero


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Genetic mutations linked to myeloproliferative neoplasms may emerge in childhood or even in utero, decades before they cause cancer, according to a late-breaking abstract presented today at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition by Jyoti Nangalia, MBBChir, and colleagues (Abstract LBA-1).

“Our preliminary findings show these cancer driver mutations were often acquired in childhood, many decades before the cancer diagnosis,” she said. “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.”

Jyoti Nangalia, MBBChir

Jyoti Nangalia, MBBChir

Genetic testing, therefore, might someday be able to identify people at risk for these cancers much earlier than current methods allow, the researchers believe.

Study Details

Philadelphia chromosome–negative myeloproliferative neoplasms are unique cancers capturing the earliest stages of tumorigenesis through disease evolution. Most patients harbor a JAK2 V617F mutation, which may be the only driver mutation or can occur in combination with other driver mutations in genes such as DNMT3A or TET2.

Study investigators, led by Dr. Nangalia, of the Wellcome Sanger Institute and University of Cambridge in the United Kingdom, traced the genetic origins of Philadelphia chromosome–negative myeloproliferative neoplasms. They first 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. Their aim was to identify the timing of driver mutations and clonal dynamics.

The researchers identified 448,553 somatic mutations and used them to construct phylogenetic trees of hematopoiesis, tracing blood cell lineages back to embryogenesis. They timed the acquisition of driver mutations, characterized the dynamics of tumor evolution, and measured clonal expansion rates over the lifetime of patients. They were able to trace the ancestry of different blood cells and estimate the time at which each patient acquired JAK2 V617F and other important mutations.

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, tracing blood cell lineages back to embryogenesis.
  • In 10 patients with these cancers, they were able to estimate the time at which each patient acquired JAK2 V617F and other important mutations.

Timeline of Mutation Acquisition

In the 10 patients they 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,” commented Dr. Nangalia.

The group also discovered that clones grow at very different rates in different individuals.

“In one patient, multiple different clones were acquired very early in life. One clone was growing at a rate of 10% per year, while another grew at 200% per year, doubling every 7 months in size,” she said.

While it is often assumed that most cancers are diagnosed within a few years of their emergence, the findings point to a more gradual, lifelong process in which a single cell acquires a cancer-linked mutation early in life and then slowly grows over decades, ultimately leading to cancer.

Dr. Nangalia and colleagues hope to eventually understand the factors that influence the different rates of cancer growth, and to determine whether this sort of process also occurs in other myeloid malignancies.  

She added, "For these patients, we calculated how many of these cancer clones would have been present in the past, and our results suggest that these clones may have been detectable up to 10 to 40 years before diagnosis. In addition to detecting the mutations, the rate at which the mutated clones grew was also very important in determining whether, and when, cancer develops...Understanding the timelines of development of different cancers is critical for efforts aimed at early cancer detection and prevention."

Commentary

Robert Brodsky, MD

Robert Brodsky, MD

The findings represent “untapped opportunities” to potentially intervene to prevent or slow the development of disease, said Robert Brodsky, MD, ASH Secretary, Professor and Director of the Division of Hematology at Johns Hopkins School of Medicine, Baltimore.

“Not only is this fascinating, but think how long a period of time we have in which to intervene. If we could slow that process down, we could change the natural history of these diagnoses. This is a tour de force piece of work,” commented Dr. Brodsky.

Disclosure: For full disclosures of the study authors, visit ash.confex.com.

 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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