Tracking how blood cancers develop over time has uncovered important genetic differences between patients whose disease stays stable while others worsen. The research also reveals how genetic information can help refine diagnoses, improve how patients with cancer are monitored in the clinic, and help doctors understand the effects of treatment, informing how regular genomic testing could be used in routine NHS care. Published today (20 April) in Cancer Discovery, researchers from the Wellcome Sanger Institute and their collaborators analysed the ancestry of blood cell populations and clinical data in patients with chronic blood cancers to understand how they evolve over decades. The data are also presented at the American Association of Cancer Research (AACR) Conference in San Diego. Myeloproliferative neoplasms (MPNs) are one example of chronic blood cancers. They are a group of rare conditions that develop in the bone marrow where blood cells are produced in an uncontrollable way. There are around 40,000 people living with MPNs, with 4,000 new cases of MPNs diagnosed in the UK each year.1 These cancers often develop slowly, driven by certain mutations – changes in DNA – sometimes occurring very early in life and acquiring additional mutations over decades.2 MPNs are typically driven by mutations in the JAK2, CALR or MPL genes but around 10 per cent of patients do not carry these mutations. Patients who do not have these typical genetic markers are currently given a cancer diagnosis based mainly on the appearance of bone marrow cells. This means some patients may receive treatment, including chemotherapy, without clear proof of an underlying blood cancer. Some patients with these chronic blood cancers feel well and only require gentle treatment while their disease remains stable, whereas others progress to more serious conditions such as leukaemia, or develop scarring within the bone marrow. However, clinicians cannot always predict which patients will worsen, or how their disease will evolve. In a new study, researchers from the Sanger Institute and their collaborators set out to understand if analysing genetic changes could help predict blood cancer progression and if patients who do not have the typical genetic markers truly have blood cancer. The researchers tracked 30 patients with chronic blood cancers, primarily MPNs, over time and combined whole-genome sequencing with detailed clinical data, including nearly 8,000 blood test results, treatment exposure and disease data.3 More than 450 samples were analysed through serial genomic monitoring, with some patients followed for up to 25 years through ongoing clinical care. This long-term follow-up, linking genomic analysis at the Sanger Institute with routine care of patients at Cambridge University Hospitals NHS Foundation Trust, enabled researchers to track how blood cell populations changed over time, providing insights into how cancers evolve more broadly. By analysing DNA from blood cells to construct 'family trees', the researchers could trace the origins of cancer clones — genetically identical cells — that eventually drove disease progression in the clinic. Firstly, by tracking the genetic changes in patients over more than a decade, the researchers found that MPNs follow distinct evolutionary patterns in populations of blood cells. Patients whose disease remained clinically stable had genetically 'steady' blood cells, which do not acquire additional mutations, whereas blood cells in those whose disease progressed developed additional changes in DNA over time. These findings suggest that disease progression in chronic blood cancers is often biologically 'encoded' years in advance and genetic mutations in blood cells are detectable long before symptoms worsen and become clinically visible. Secondly, by analysing the 'family trees' constructed from around 200 blood cell genomes from those who do not have the typical genetic markers of MPNs, they found patterns in blood cell evolution that are consistent with normal ageing rather than any cancer-driven processes. This challenges the current view that all patients with certain bone marrow features have a true blood cancer. This suggests that some individuals may be currently classified within this disease group when they actually have features distinct from a true blood cancer, highlighting the need to reconsider how clinicians manage such individuals. These findings support new British Society for Haematology guidelines on investigating patients without JAK2, CALR or MPL mutations, which aim to improve diagnosis and management for this group.4,5 Overall, the study has several direct clinical implications and highlights the importance of using genomic information in cancer clinics, which may support the development of more precise therapies. The researchers hope that in the future, clinicians could monitor patients using regular genetic tests in the clinic in order to identify those at high risk of disease progression years before and intervene at an earlier stage. Dr Daniel Leongamornlert, first author at the Wellcome Sanger Institute, said: "We followed patients with myeloproliferative neoplasms over many years and used genome sequencing and clinical history to trace how blood cell populations changed over time. By reconstructing the ancestry of cells, we were able to see different evolutionary patterns between patients who had stable disease compared to others who progressed." Dr Dani Skirrow, Research Information Manager at Cancer Research UK, who part-funded the study, said: "We're in a golden age of research where advances in technology mean we can rapidly read DNA to find the errors in the code that can lead to cancer. Collaboratively, our researchers have read huge amounts of DNA to build up a detailed picture of how certain blood cancers can start, grow and behave, revealing some changes that could help us predict cancer years in advance. This type of discovery research is essential to improve how we monitor people at risk of blood cancer, and to help us find better ways to prevent, detect and treat the disease so people can live longer, better lives." Dr Jyoti Nangalia, senior author at the Wellcome Sanger Institute and Honorary Consultant Haematologist at Cambridge University Hospitals NHS Foundation Trust, said: "These are patients we have cared for and followed in our clinic for over 15 years. It can be incredibly difficult to predict how their cancers might change over time. By combining long-term clinical care with regular genomic analysis, we've been able to watch how the genetic code of their disease evolves in advance of clinical changes. The patterns we have found will help doctors develop better monitoring strategies, refine diagnosis and lead to better patient outcomes in the long run." Alan Everitt, 77, a patient at Cambridge University Hospitals NHS Foundation Trust, was first diagnosed with a type of MPN called essential thrombocythaemia (ET) in 1992. ET is a rare blood cancer that causes the body to produce too many platelets – blood cells involved in clotting. Over time, Alan's condition has progressed to myelofibrosis, which causes scarring of the bone marrow, alongside the development of recurrent skin cancers. Alan Everitt, from Hardwick, Cambridgeshire, said: "It's been reassuring to be cared for over so many years by both the haematology and plastic surgery teams at Addenbrooke's Hospital in Cambridge. I have always felt well supported and I'm grateful for the care and feedback at every step. Living with a blood cancer for such a long time has come with many challenges, and I hope that taking part in this research will help make a difference for future patients whose cancer is likely to progress over time, as mine has." |
