Genome analysis goes back in time to trace genesis of blood cancers

Single point mutations that drive the development of myeloproliferative neoplasms (MPNs) can be traced back to decades before the diagnosis, according to a recent study. Such mutations also give the cells that harbour them a selective advantage.

To trace back the history of MPN, the researchers zeroed in on the V617F mutation of the JAK2 gene, which is widely known in the field to be an underlying driver of the malignancy’s molecular pathogenesis.

Haematopoietic stem and progenitor cells (HSPCs) were sampled from seven newly diagnosed patients (three with polycythaemia vera [PV] and four with essential thrombocythaemia [ET]) and subjected to single-cell transcriptomic profiling. First focusing on two ET patients, patterns of somatic mutations were used to reconstruct the lineage trees of haematopoietic stem cells (HSCs) bearing the JAK2 mutation.

In both patients, the researchers found two distinct clades of cells that were differentiated primarily by the presence of the JAK2-V617F mutation, suggesting that this singular change was the event that initiated MPN. There were also several mutations shared across the JAK2 mutant cells, further pointing to a common ancestor that had undergone clonal expansion. [Cell Stem Cell 2021;28:514-523.e9]

Notably, the V617F genesis event occurred long before the diagnosis. In the younger patient, who was enrolled at 34 years of age, the mutation took place approximately 25 years before, when the patient was around 9 years old. In the older patient, who enrolled at 63 years of age, the initiating event took place when they were 19 years old, around 40 years before.

Using computational modelling techniques, the researchers also traced the progression of the disease and the expansion of the mutant cells. They found that in both patients, fewer than 100 cells bearing V617F were present in the first decade following the first mutation. Expansion happened exponentially afterward.

The models likewise suggested that the V617F mutation improves the relative fitness of the cells harbouring them, giving them strong selective advantage over JAK2 wildtype cells.

In the younger ET patient, the point mutation had an inferred fitness benefit of 63±15 percent, while in the older ET patient, fitness improved by 44±13 percent. However, such fitness estimates were obtained from computational models limited by its specific assumptions.

“Many cancers start when a genetic alteration arises in a single cell and confers a fitness advantage over other cells. By the time the disease manifests clinically, this cell has expanded to millions of cells or more,” the researchers said.

“Naturally occurring somatic mutations provide a glimpse into the history of cancer in each individual, revealing when the driver mutations first occurred, how the population of cancer cells expanded, and how their proliferation and differentiation dynamics differ from healthy cells,” they added.

“The framework we developed to harness somatic mutations as a clock to reconstruct the lineage tree of cancer cells and follow the differentiation trajectories of their progenies is broadly applicable in oncology,” they said.