ASH20: Genetic Mutations Could Help Predict Cancer Symptoms Decades in Advance

By Mary Ellen Schneider

Using whole genome sequencing, researchers have traced the genetic origins of myeloproliferative neoplasms to early childhood, and in some cases all the way back to the time in utero.

The findings, which were presented during the late breaking abstract session at the annual meeting of the American Society of Hematology, suggest that the genetic predictors of disease could be detected decades before patients experience disease symptoms, opening the door for preventive approaches.

“Right from the start of life, as our cells are dividing, mutations are being acquired and they are being passed down from generation to generation such that at any one snapshot in time in our life, the mutations within individual cells represent natural bar codes that can be used to trace back the ancestry of those cells right to the start of life,” said Jyoti Nangalia, MBBChir, of Wellcome-MRC Cambridge Stem Cell Institute in the United Kingdom, who presented the study findings.

In the study, researchers obtained blood and bone marrow samples from 10 patients with Philadelphia-negative myeloproliferative neoplasms and grew single cell-derived hematopoietic colonies. They then performed whole genome sequencing on each colony, ultimately performing 900 whole-genome sequences (Abstract LBA-1).

They also identified somatic mutations, which were used to construct phylogenetic “trees.” The researchers were able to determine the timing of driver mutation acquisition, characterize the dynamics of tumor evolution, and measure clonal expansion rates over the lifetime of patients in the study.

They found that JAK2V617F was generally acquired in utero or childhood in all patients in whom the mutation was the first or the only driver mutation. The acquisition occurred as early as a few weeks after conception or as late as 11 years old. But the mean latency period between JAK2V617F acquisition and clinical presentation of MPN was 34 years. Acquisition of additional driver mutations was separated by decades.

Researchers also identified DNMT3A mutations, which are linked to age-related clonal hematopoiesis. DNMT3A mutations occurred as a first driver event, subsequent to mutated-JAK2, and as independent clones representing clonal hematopoiesis in MPN patients. The DNMT3A mutations could also be acquired in utero or childhood.

The researchers also obtained longitudinal blood samples from the 10 patients and re-sequenced the mutations seen in the phylogenetic trees in the whole blood. By combining the mutant clonal fractions in blood with the pattern of branching in the trees, they were able to infer the rate at which those clones were growing over the life of the patient.

“We found that clone rates varied hugely,” Dr. Nangalia said. For instance, in a single patient they identified one clone that was growing at a rate of 10% per year, while another clone was growing 233% per year, representing a doubling in size every 7 months.

When the research team examined clones that had the same genetic composition – such as JAK2V617F as a driver mutation – they found that it grew at different rates in different patients, “suggesting that there are factors other than JAK2 that determine the consequences of acquiring it in individual patients,” Dr. Nangalia said.

But perhaps most important, Dr. Nangalia said, they found that the rate of clonal growth determined the latency period to diagnosis. Patients with very slow growth rates took 50 years to present with disease symptoms, while patients with faster clonal growth rates presented as quickly as 10 years after acquisition.

Featured News
(NYU Langone Hospital) Feb 16, 2021 - A test that monitors blood levels of DNA fragments released by dying tumor cells may serve as an accurate early indicator of treatment success in the late stages of one of the most aggressive forms of...
(Morningstar) Feb 24, 2021 - Kura Oncology, Inc. today announced that its investigational drug, tipifarnib, has been granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) for the treatment of patients with...
(The Scientist) Feb 17, 2021 - Scientists are realizing that many “silent” mutations might not be so silent after all. The authors of a study describe a synonymous mutation in the gene BAP1 that was associated with a...
(Seagen) Feb 18, 2021 - Seagen Inc. and Astellas Pharma Inc. today announced completion of submissions for two supplemental Biologics License Applications (sBLAs) to the U.S. Food and Drug Administration (FDA) for PADCEV® (enfortumab...
(BeiGene) Feb 17, 2021 - BeiGene, Ltd., a commercial-stage biotechnology company focused on developing and commercializing innovative medicines worldwide, today announced that the U.S. Food and Drug Administration (FDA) has accepted a...