Study uncovers role of genetic variants in blood cancer development

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Scientists have used large scale data analysis to investigate why only some people with a common mutation go on to develop certain rare blood cancers.

Researchers from the Wellcome Sanger Institute, the University of Cambridge and other partners combined three key data sets for a Nature Genetics study focusing on myeloproliferative neoplasms (MPNs), a group of rare chronic blood cancers.

MPNs are characterized by overproduction of mature blood cells and have been linked to random somatic mutations in certain genes, including in a gene called JAK2. Mutated JAK2 is commonly found in the global population as clonal hematopoiesis; most carriers don't develop “disease-defining” characteristics of MPN.

Little was previously known about why only a minority of individuals with mutated JAK2 develop more severe hematological manifestations of MPN and the factors that influence blood count heterogeneity in MPNs.

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

“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,” said Dr. Jyoti Nangalia, co-senior author from the Wellcome Sanger Institute and the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge.

“Our hope is that this information can be incorporated into future disease prediction efforts,” Nangalia said.

Doctors use blood tests showing the number of blood cells and look for genetic mutations inside them to diagnose MPNs. There is a wide range of natural variation among individuals’ blood cells, which can affect the number of blood cells a person has and their particular traits.

Multiple genes can influence blood cell features in an individual. Analysis of variation produces a genetic risk score for how likely that individual is to develop a disease over their lifetime.

In the Nature Genetics study, researchers combined information on the known somatic driver mutations in MPN, inherited genetic variants, and genetic risk scores from individuals with MPN to obtain a more complete picture of how these variants combine to cause blood disorders. 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.

“By analyzing two large MPN disease cohorts and UK Biobank (UKBB), we provide new insights into the interaction between germline polygenic variation involved in basic hematopoiesis and clonal selection on somatic driver mutations in blood and describe how this interaction can influence the phenotype of subsequent blood cancer,” the authors wrote. 

“Our results highlight an independent and causal new component of the overall susceptibility to clonal disease and provide a new framework for considering an individual’s genetic background in the context of their clinical presentation,” they conclude.

The research was funded by Cancer Research UK and Wellcome.

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