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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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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̽��ֱ�� of Cambridge - Jyoti Nangalia

Role of inherited genetic variants in rare blood cancer uncovered

Researchers discover new test for chronic blood cancers