Researchers trace the origin of blood cancer to early childhood, decades before diagnosis
Dr Jyoti Nangalia - University of Cambridge, Cambridge, UK
As haematologists treating patients with blood cancers, one of the most common questions that we get asked by our patients is, ‘How long have I had it for?’ or ‘When did the cancer start? How fast is it growing?’ or, indeed, ‘Is it still growing?’ So it’s these really fundamental questions that we wanted to answer in this study and we looked at a particular cancer to first address these questions. The cancers are called myeloproliferative neoplasms and they are a chronic form of blood cancer that is fairly common within the population and increases as people get older.
We took ten patients with myeloproliferative neoplasms, they had presented with disease at different ages, right from their 20s to some patients in their 70s, and they had a variety of different types of myeloproliferative neoplasms. We took individual blood cells from these patients and then we grew each individual blood cell into a colony of cells. Then what we did is undertake whole genome sequencing, so sequenced all the DNA within each of these colonies.
Effectively that gave us multiple whole genome sequences from each individual patient. Then what we did is construct what’s essentially a family tree of mutations across the blood cells from each individual patient that, in effect, told us how the cells were related to one another. That then allowed us to time the driver mutations that caused these cancers to whichever point in the patient’s life when they were occurring. It also allowed us to understand when the cancer started to grow and at what speed it was growing over the lifetime of the patient.
What we found in this study was completely unexpected. Normally our intuition tells us that the genetic changes that drive the cancer perhaps occur a few years before the cancer and then the patient presents with a clinical manifestation and to clinic with abnormalities, either complications or abnormalities in their blood counts. What we found was the complete opposite, we found that the cancer causing driver mutations are acquired very early in life. The first event in many of our patients was in childhood or indeed in utero. So, for example, the JAK2 mutation that drives the majority of myeloproliferative neoplasms was acquired in childhood or in utero. Indeed, DNMT3A mutations which are also prevalent in these conditions and are actually very common in a phenomenon called clonal haematopoiesis [?], which is something that you develop in your blood as you get older, this was also occurring very, very early and in some of our patients the earliest estimates were within days to weeks of conception in utero.
So what this is actually telling us is that we acquire these mutations very early and it is a period of lifelong outgrowth that then eventually leads to complications from this cancer. What we also found was that these cancers can, as they grow, pick up additional driver mutations and often those additional mutations can be separated by decades across the patient’s life. We then were able to estimate how fast these cancers grew and we found that the cancers were growing at different rates in different individuals. Even when you looked at the same clones, such as a clone that had a JAK2 mutation, it was growing at different rates in different individuals, telling us that there’s something else that predetermines how fast a cancer clone is going to grow – perhaps your germline make-up or the environment within which these cells are growing.
What was quite striking, though, is that the faster the clone was growing, the quicker the patient presented with disease. So the rate of growth of the clone was strongly proportional to the latency to a diagnosis.
In addition, what we found is that because we could estimate how fast these clones were growing and when these mutations that caused the cancer occurred, we could backtrack and estimate when would we have been able to detect these cancer-driving mutations in this patient. We estimate that we would have been able to detect these mutations 10-40 years before diagnosis which really then tells us that if we could detect these mutations early and we could then estimate their growth rates, we could potentially in the future predict which individuals within a healthy population are on a path to future clinical complications.
In this particular blood cancer many patients present with complications from their cancer at diagnosis, usually in the form of blood clots either in arteries or veins. So if we know that actually these cancers have been growing for a very long time in these individuals then it begs the question, should be we be identifying such individuals within the healthy population, estimating which patients are on track to having complications and start to treat them early, perhaps with very safe agents such as aspirin or other agents that would prevent or reduce the risk of a blood clot.
The other thing is that there are some agents in clinic that we use that are able to reduce the size of the tumours. It also raises the question whether if we started to use those, or tested their use at an earlier stage, might they be of benefit to stop or halt the rate of growth of these cancers.
The other thing it begs the question is when should we be diagnosing these cancers, given that they are present lifelong really? At what stage should we be considering an earlier diagnosis in these patients?
One other thing we’d like to add is that the method that we used to time the origins and the trajectory of this cancer can actually be used in other blood cancers and, indeed, in other solid tumours. So this really now asks whether all blood cancers evolve in this way or whether there are a variety of different paths to different cancers. So it would be really interesting to look at acute leukaemia or perhaps lymphoid cancers to see wat is the trajectory to these different cancers. That knowledge is critical for programmes aimed at early detection and prevention of cancer.
