̽��ֱ�� of Cambridge - blood cancer

Role of inherited genetic variants in rare blood cancer uncovered

jg533 — Wed, 17 Jan 2024 10:03:16 +0000

Large-scale genetic analysis has helped researchers uncover the interplay between cancer-driving genetic mutations and inherited genetic variants in a rare type of blood cancer.

Researchers from the ̽��ֱ�� of Cambridge, Wellcome Sanger Institute, and collaborators, combined various comprehensive data sets to understand the impact of both cancer-driving spontaneous mutations and inherited genetic variation on the risk of developing myeloproliferative neoplasms (MPN).

̽��ֱ��study, published in the journal Nature Genetics, describes how inherited genetic variants can influence whether a spontaneous mutation in a particular gene increases the risk of developing this rare blood cancer.

This analysis has an impact on current clinical predictions of disease development in individuals. Further research is required to understand the biological mechanisms behind how these inherited genetic variants influence the chances of developing rare blood cancer. In the future, this knowledge could aid drug development and interventions that reduce the risk of disease.

Myeloproliferative neoplasms, MPNs, are a group of rare, chronic, blood cancers. There are around 4,000 cases of MPN in the UK each year. These occur when the bone marrow overproduces blood cells, which can result in blood clots and bleeding. MPNs can also progress into other forms of blood cancer, such as leukaemia.

In the population, there is a large amount of natural variation between individuals’ blood cells, which can affect the amount of blood cells a person has and their particular traits. This is because multiple different genes can influence blood cell features in an individual. During routine blood tests, researchers take known information about these genes and analyse the variation to give a genetic risk score, which is how likely that individual is to develop a disease over their lifetime.

MPNs have been linked to random somatic mutations in certain genes including in a gene called JAK2. However, mutated JAK2 is commonly found in the global population, and the vast majority of these individuals do not have or go on to develop MPN.

Whilst previous studies have identified over a dozen associated inherited genetic variants that increase the risk of MPN, these studies insufficiently explain why most individuals in the population do not go on to develop MPN.

This new study, from the Wellcome Sanger Institute and collaborators, combined information on the known somatic driver mutations in MPN, inherited genetic variants, and genetic risk scores from individuals with MPN.

They found that the inherited variants that cause natural blood cell variation in the population also impact whether a JAK2 somatic mutation will go on to cause MPN. They also found that individuals with an inherited risk of having a higher blood cell count could display MPN features in the absence of cancer-driving mutations, thus, mimicking disease.

Dr Jing Guo, from the ̽��ֱ�� of Cambridge and the Wellcome Sanger Institute and first author of the study, said: “Our large-scale statistical study has helped fill the knowledge gaps in how variants in DNA, both inherited and somatic, interact to influence complex disease risk. By combining these three different types of datasets we were able to get a more complete picture of how these variants combine to cause blood disorders.”

Professor Nicole Soranzo, co-senior author from the ̽��ֱ�� of Cambridge, the Wellcome Sanger Institute, and Human Technopole, Italy, said: “There has been increasing realisation that human diseases have complex causes involving a combination of common and rare inherited genetic variants with different severity.

“We have previously shown that variation in blood cell parameters and function has complex genetic variability by highlighting thousands of genetic changes that affect different gene functions. Here, we show for the first time that common variants in these genes also affect blood cancers, independent of causative somatic mutations. This confirms a new important contribution of normal variability beyond complex disease, contributing to our understanding of myeloproliferative neoplasms and blood cancer more generally.”

Dr Jyoti Nangalia, co-senior author from the Wellcome-MRC Cambridge Stem Cell Institute at the ̽��ֱ�� of Cambridge, and the Wellcome Sanger Institute, said: “We have a good understanding of the genetic causes of myeloproliferative neoplasms. In fact, many of these genetic mutations are routine diagnostic tests in the clinic. However, these mutations can often be found in healthy individuals without the disease.

“Our study helps us understand how inherited DNA variation from person to person can interact with cancer-causing mutations to determine whether disease occurs in the first place, and how this can alter the type of any subsequent disease that emerges. Our hope is that this information can be incorporated into future disease prediction efforts.”

This research was funded by Cancer Research UK and Wellcome.

Reference

J Guo, K Walter, P M Quiros, et al. ‘Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms.’ Jan 2024, Nature Genetics. DOI: 10.1038/s41588-023-01638-x

Adapted from a press release by the Wellcome Sanger Institute

Combining three different sources of genetic information has allowed researchers to further understand why only some people with a common mutation go on to develop rare blood cancer.

Our hope is that this information can be incorporated into future disease prediction efforts

Jyoti Nangalia

Photo by Sangharsh Lohakare on Unsplash

DNA

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Order matters: sequence of genetic mutations determines how cancer behaves

cjb250 — Wed, 11 Feb 2015 22:00:00 +0000

Most of the genetic mutations that cause cancer result from environmental ‘damage’ (for example, through smoking or as a result of over-exposure to sunlight) or from spontaneous errors as cells divide. In a study published today, researchers at the Department of Haematology, the Cambridge Institute for Medical Research and the Wellcome Trust/Medical Research Council Stem Cell Institute show for the first time that the order in which such mutations occur can have an impact on disease severity and response to therapy.

̽��ֱ��researchers examined genetically distinct single stem cells taken from patients with myeloproliferative neoplasms (MPNs), a group of bone marrow disorders that are characterised by the over-production of mature blood cells together with an increased risk of both blood clots and leukaemia. These disorders are identified at a much earlier stage than most cancers because the increased number of blood cells is readily detectable in blood counts taken during routine clinical check-ups for completely different problems.

Approximately one in ten of MPN patients carry mutations in both the JAK2 gene and the TET2 gene. By studying these individuals, the research team was able to determine which mutation came first and to study the effect of mutation order on the behaviour of single blood stem cells.

Using samples collected primarily from patients attending Addenbrooke’s Hospital, part of the Cambridge ̽��ֱ�� Hospitals, researchers showed that patients who acquire mutations in JAK2 prior to those in TET2 display aberrant blood counts over a decade earlier, are more likely to develop a more severe red blood cell disease subtype, are more likely to suffer a blood clot, and their cells respond differently to drugs that inhibit JAK2.

Dr David Kent, one of the study’s lead authors, says: “This surprising finding could help us offer more accurate prognoses to MPN patients based on their mutation order and tailor potential therapies towards them. For example, our results predict that targeted JAK2 therapy would be more effective in patients with one mutation order but not the other.”

Professor Tony Green, who led the study, adds: “This is the first time that mutation order has been shown to affect any cancer, and it is likely that this phenomenon occurs in many types of malignancy. These results show how study of the MPNs provides unparalleled access to the earliest stages of tumour development (inaccessible in other cancers, which usually cannot be detected until many mutations have accumulated). This should give us powerful insights into the origins of cancer.”

Work in the Green Lab is supported in part by Leukaemia and Lymphoma Research and Cancer Research UK.

Dr Matt Kaiser, Head of Research at Leukaemia & Lymphoma Research, said: “We are becoming more and more aware that a cancer’s genetic signature can vary from patient to patient, and we are becoming better at personalising treatment to match this. ̽��ֱ��discovery that the order in which genetic errors occur can have such a big impact on cancer progression adds an important extra layer of complexity that will help tailor treatment for patients with MPNs. ̽��ֱ��technology to do this sort of study has been available only recently and it shows once again how pioneering research into blood cancers can reveal fundamental insights into cancer in general.”

Dr Áine McCarthy, Science Information Officer at Cancer Research UK, says: “ ̽��ֱ��methods used in this pioneering research could help improve our understanding of how cancer cells develop mutations and when they do so. This interesting study suggests that the order in which genetic faults appear can affect how patients respond to different drugs – this insight could help doctors personalise treatment to make it more effective for each patient.”

Reference
Ortmann, CA and Kent, DG et al. ̽��ֱ��Impact of Mutation Order on Myeloproliferative Neoplasms. NEJM; 11 Feb 2015

Additional funding came from the Kay Kendall Leukaemia Fund; the NIHR Cambridge Biomedical Research Centre; the Cambridge Experimental Cancer Medicine Centre; the Leukemia & Lymphoma Society of America; the Canadian Institutes of Health Research; and the Lady Tata Memorial Trust.

̽��ֱ��order in which genetic mutations are acquired determines how an individual cancer behaves, according to research from the ̽��ֱ�� of Cambridge, published today in the New England Journal of Medicine.

This is the first time that mutation order has been shown to affect any cancer, and it is likely that this phenomenon occurs in many types of malignancy

Tony Green

geralt

Red blood cells (illustration)

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Computer model of blood development could speed up search for new leukaemia drugs

cjb250 — Mon, 09 Feb 2015 16:00:00 +0000

̽��ֱ��human body produces over 2.5 million new blood cells during every second of our adult lives, but how this process is controlled remains poorly understood. Around 30,000 new patients each year are diagnosed with cancers of the blood each year in the UK alone. These cancers, which include leukaemia, lymphoma and myeloma, occur when the production of new blood cells gets out of balance, for example if the body produces an overabundance of white blood cells.

Biomedical scientists from the Wellcome Trust-MRC Cambridge Stem Cell Institute and the Cambridge Institute for Medical Research collaborated for the past 2 years with computational biologists at Microsoft Research and Cambridge ̽��ֱ��’s Department of Biochemistry. This interdisciplinary team of researchers have developed a computer model to help gain a better understanding of the control mechanisms that keep blood production normal. ̽��ֱ��details are published today in the journal Nature Biotechnology.

“With this new computer model, we can carry out simulated experiments in seconds that would take many weeks to perform in the laboratory, dramatically speeding up research into blood development and the genetic mutations that cause leukaemia,” says Professor Bertie Gottgens whose research team is based at the ̽��ֱ��’s Cambridge Institute for Medical Research.

Dr Jasmin Fisher from Microsoft Research and the Department of Biochemistry at the ̽��ֱ�� of Cambridge says: “This is yet another endorsement of how computer programs empower us to gain better understanding of remarkably complicated processes. What is ground-breaking about the current work is that we show how we can automate the process of building such programs based on raw experimental data. It provides us with a blueprint to develop computer models relevant to other human diseases including common cancers such as breast and colon cancer.”

To construct the computer model, PhD student Vicki Moignard from the Stem Cell Institute measured the activity of 48 genes in over 3,900 blood progenitor cells that give rise to all other types of blood cell: red and white blood cells, and platelets. These genes include TAL1 and RUNX1, both of which are essential for the development of blood stem cells, and hence to human life.

Computational biology PhD student Steven Woodhouse then used the resulting dataset to construct the computer model of blood cell development, using computational approaches originally developed at Microsoft Research for synthesis of computer code. Importantly, subsequent laboratory experiments validated the accuracy of this new computer model.

One way the computer model can be used is to simulate the activity of key genes implicated in blood cancers. For example, around one in five of all children who develop leukaemia has a faulty version of the gene RUNX1, as does a similar proportion of adults with acute myeloid leukaemia, one of the most deadly forms of leukaemia in adults. ̽��ֱ��computer model shows how RUNX1 interacts with other genes to control blood cell development: the gene produces a protein also known as Runx1, which in healthy patients activates a particular network of key genes; in patients with leukaemia, an altered form of the protein is thought to suppress this same network. If the researchers change the ‘rules’ in the network model, they can simulate the formation of abnormal leukaemia cells. By tweaking the leukaemia model until the behaviour of the network reverts back to normal, the researchers believe they can identify promising pathways to target with drugs.

Professor Gottgens adds: “Because the computer simulations are very fast, we can quickly screen through lots of possibilities to pick the most promising ones as pathways for drug development. ̽��ֱ��cost of developing a new drug is enormous, and much of this cost comes from new candidate drugs failing late in the drug development process. Our model could significantly reduce the risk of failure, with the potential to make drug discovery faster and cheaper.”

̽��ֱ��research was supported by the Medical Research Council, the Biotechnology and Biological Sciences Research Council, Leukaemia and Lymphoma Research, the Leukemia and Lymphoma Society, Microsoft Research and the Wellcome Trust.

Dr Matt Kaiser, Head of Research at UK blood cancer charity Leukaemia & Lymphoma Research, which has funded Professor Gottgens’ team for over a decade, said: “For some leukaemias, the majority of patients still ultimately die from their disease. Even for blood cancers for which the long-term survival chances are fairly good, such as childhood leukaemia, the treatment can be really gruelling. By harnessing the power of cutting-edge computer technology, this research will dramatically speed up the search for more effective and kinder treatments that target these cancers at their roots.”

Reference
Moignard, V et al. Decoding the regulatory network of early blood development from single-cell gene expression measurements. Nature Biotech; 9 Feb 2015.

̽��ֱ��first comprehensive computer model to simulate the development of blood cells could help in the development of new treatments for leukaemia and lymphoma, say researchers at the ̽��ֱ�� of Cambridge and Microsoft Research.

With this new computer model, we can carry out simulated experiments in seconds that would take many weeks to perform in the laboratory

Bertie Gottgens

E. M. Unit, Royal Free Hospital

SEM image of normal red blood cells, computer-coloured red

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Researchers discover new test for chronic blood cancers

sj387 — Tue, 10 Dec 2013 15:27:54 +0000

A simple blood test will soon be able to catch the vast majority of a group of chronic blood cancers, a new study reveals. Although around 60 per cent of cases can be identified with the current blood test, scientists did not know what caused the other cases and therefore could not test for it. Cambridge researchers have now identified a new cancer gene which accounts for the other 40 per cent of these chronic blood cancers. ̽��ֱ��research was published today, 10 December, in the New England Journal of Medicine.

Professor Tony Green, from the ̽��ֱ�� of Cambridge’s Cambridge Institute for Medical Research and Department of Haematology, who led the research said: “Diagnosing these chronic blood cancers is currently difficult and requires multiple tests, some of which are invasive and painful. Now, most patients with a suspected blood cancer will be able to be given a diagnosis after a simple blood test.”

This group of chronic blood cancers – which affect an estimated 30,000 people annually in the UK – cause the over-production of red blood cells and platelets. These changes result in an increased incidence of blood clots which can be devastating when strokes or heart attacks occur. Although many patients can live for years with few or no symptoms, in some patients the disorders can become more aggressive with time and may even develop into acute leukaemia.

In 2005 scientists identified the JAK2 gene, mutationt in which are associated with around 60 per cent of blood cell disorders. Based on these findings a blood test was developed which transformed the way these blood disorders are diagnosed. Unfortunately, because the gene was only found in a little over half of people with chronic blood cancers, individuals who tested negative for the JAK2 gene would then have to undergo a battery of protracted, invasive testing to determine if they indeed had one of these disorders.

In the new study, led by the ̽��ֱ�� of Cambridge and the Wellcome Trust Sanger Institute and supported by Leukaemia & Lymphoma Research together with the Kay Kendall Leukaemia Fund, scientists identified a new gene, CALR, which is altered in the other 40 per cent of blood disorders. For the research, the scientists sequenced the DNA of patients with chronic blood disorders. By analysing the DNA sequence, they were able to identify CALR as a new cancer gene which, when mutated, results in chronic blood cancers. Additionally, they found that patients with the CALR mutation – unlike those with the JAK2 mutation – had higher platelet counts and lower haemoglobin levels.

Peter Campbell from the Sanger Institute, who co-led the research, said: “There is now a sense of completeness with these disorders – the vast majority of our patients can now have a definitive genetic diagnosis made. In the next year or two, we will see these genetic technologies increasingly used in the diagnosis of all cancers, especially blood cancers.”

Dr Jyoti Nangalia co-first author of the study from the ̽��ֱ�� of Cambridge said: “Not only will the identification of CALR lead to a new, less invasive test, we also hope that it can lead to new treatments – just as the discovery of JAK2 did. ̽��ֱ��CALR gene is involved in a cell function – aiding with the folding of proteins made by the cell - which has not implicated in these disorders before, so our research raises as many questions as it answers.”

A new test for blood cancers will catch many more cases than the present test that identifies only 60 per cent.

Not only will the identification of CALR lead to a new, less invasive test, we also hope that it can lead to new treatments

Dr Jyoti Nangalia

Nephron

Micrograph of a plasmacytoma, a hematological malignancy

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