“Life Histories of Myeloproliferative Neoplasms Inferred from Phylogenies”, 2022-01-20 (; similar):
Mutations in cancer-associated genes drive tumour outgrowth, but our knowledge of the timing of driver mutations and subsequent clonal dynamics is limited.
Here, using whole-genome sequencing of 1,013 clonal haematopoietic colonies from 12 patients with myeloproliferative neoplasms, we identified 580,133 somatic mutations to reconstruct haematopoietic phylogenies and determine clonal histories.
Driver mutations were estimated to occur early in life, including the in utero period. JAK2V617F was estimated to have been acquired by 33 weeks of gestation to 10.8 years of age in 5 patients in whom JAK2V617F was the first event. DNMT3A mutations were acquired by 8 weeks of gestation to 7.6 years of age in 4 patients, and a PPM1D mutation was acquired by 5.8 years of age. Additional genomic events occurred before or following JAK2V617F acquisition and as independent clonal expansions. Sequential driver mutation acquisition was separated by decades across life, often outcompeting ancestral clones. The mean latency between JAK2V617F acquisition and diagnosis was 30 years (range 11–54 years). Estimated historical rates of clonal expansion varied substantially (3%–190% per year), increased with additional driver mutations, and predicted latency to diagnosis.
Our study suggests that early driver mutation acquisition and life-long growth and evolution underlie adult myeloproliferative neoplasms, raising opportunities for earlier intervention and a new model for cancer development.
When someone is diagnosed with cancer, it’s a natural response for them to wonder what they did wrong, and how they could have avoided it…It’s clear that there are mutations in the stem cells (“driver mutations” that lead to a cancer phenotype), and for many years it appeared that these might occur late in life and not that long before diagnosis. The studies of increased leukemia risk in survivors of the Hiroshima and Nagasaki atomic bombings originally supported this view, but long-term follow-up (see that link) shows a complex situation with regard to radiation exposure, age at the time of the bombings, time elapsed since 1945, and the type of leukemia that developed. And it’s long been known that people who do not show signs of actual leukemia can harbor one or more of these driver mutations. Some of these people do indeed go on to develop MPNs, which suggests that there might be a longer “multi-hit” process that could go on for many years.
This work supports that idea. The team studies 12 MPN patients, whose tissue samples provided over a thousand different clones of malignant blood cells. Sequencing these turned up over 580,000 mutations (!), and the paper puts these into a phylogenetic framework to reconstruct the sequence of what the key mutations were and when they might have taken place. Using rates of mutation as a clock, some of them appear to go back even to before birth—the key JAK2V617F mutation, long associated with these malignancies, is estimated to have shown up anywhere from the 33rd week of gestation up to the age of 11. The DNMT3 mutation, similarly, seems to have appeared from the 8th week of gestation (!) out to about the age of 8. Additional driver mutations layer on top of these early events over the years to come—the mean latency between the JAK2 mutation and diagnosis of cancer, for example, was about 30 years.
…But in all cases, it seems clear that it takes many years for MPNs to develop—the diagnoses that are made in the clinic are capturing the end result of what is often a decades-long process of accumulated mutations and clonal expansion. This suggests that targeting therapies towards these mutated cells earlier in life, before the patients involved even have cancer at all, could be a really useful strategy. And it also suggests that this framework doesn’t apply only to blood cancers, either (it’s just easier to prove there).]
[cf. “Inequality in genetic cancer risk suggests bad genes rather than bad luck”, 2017/ et al 2017]