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Clonal Hematopoiesis Longitudinal Study Reveals High-Risk Mutations for Developing Cancer

NEW YORK — A team of researchers from the Netherlands has mapped the evolution of clonal hematopoiesis (CH) in thousands of individuals in order to shed light on how hematological malignancies develop.

People with CH — the clonal expansion of mutated hematopoietic stem and progenitor cells — may be at increased risk of blood cancers. However, the molecular and environmental mechanisms underlying the evolution of CH and its progression to cancer are not well understood, Joop Jansen of Radboud University Medical Center and Gerwin Huls of the University of Groningen wrote in a paper appearing in Cancer Cell on Thursday.

For their study, the researchers collected 7,045 blood DNA samples from 3,359 participants in the prospective population-based Lifelines cohort at two time points nearly three years apart. Participants ranged in age from 60 to 91 years, as CH is more prevalent in older age groups, and about a third had blood count abnormalities such as various forms of cytopenia and cytosis.

The researchers then conducted error-corrected targeted next-generation sequencing of 27 malignancy-associated genes using single-molecule molecular inversion probes on the samples to understand how different clones and clonal mutations behaved over time.

Based on their findings, the authors were also able to pinpoint how different CH clones expanded over time and affected cancer risk. While mutations in DNMT3A and TP53 were associated with limited clonal expansion, mutations in genes involved in the splicing machinery and in JAK2 led to much higher growth rates.

The researchers noted that DNMT3A mutations did not raise the risk for acquiring new mutations and also did not increase myeloid malignancy risk. TP53 mutations, on the other hand, led to minimal clonal growth but was linked to a high propensity of developing hematological malignancies.

"This finding was striking," Isabelle van Zeventer, a researcher at the University of Groningen and a lead author of the study, told GenomeWeb. "We know that DNMT3A is the most common CH mutation, but people with this mutation are not at high risk of cancer."

Overall, the findings showed that spliceosome, TP53, JAK2, and K/NRAS mutations conferred the highest risk for myeloid cancer.

"These clones have a high likelihood to result in early disturbance of hematopoiesis at older age that deserves clinical attention and monitoring," the authors wrote.

The researchers also saw that expansion rates for clones with similar genetic makeup varied substantially between participants, indicating that clonal dynamics involve a complex interplay between inherent variant fitness and host factors or physiological circumstances, according to the authors. They noted that variability in overall CH growth rate was not determined by classical cancer risk factors like smoking, sex, and body mass index.

Highlighting the limitations of the study, the authors pointed out that the size of their dataset did not allow them to evaluate the association between risk factors and the expansion of specific gene mutations.

"The dynamic contribution of other contextual factors such as differences in [hematopoietic stem and progenitor cell] lineage bias, inflammatory conditions, and germline variation, and the effect of such triggers on specific gene mutations, needs to be established in future studies," they noted.