05 February 2024

British scientists have found a relationship between cancer-driving genetic mutations and inherited genetic variants in myeloproliferative neoplasms (MPNs).

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

The study, published in Nature Genetics, describes how inherited genetic variants can influence a spontaneous mutation in a particular gene increasing the risk of developing MPN.

The team say their findings change how clinicians can predict disease development in individuals. Further research is needed to understand the biological mechanisms behind how these inherited genetic variants influence the chances of developing rare blood cancer, they say.

MPNs occur when the bone marrow overproduces blood cells, resulting in blood clots and bleeding. They have been linked to random somatic mutations in certain genes, including JAK2. However, mutated JAK2 is commonly found in the population, and the vast majority do not go on to develop MPN, the researchers say.

In this study, the team combined information on the known somatic driver mutations in MPN, inherited genetic variants, and genetic risk scores from individuals with MPN.

They found the inherited variants that cause natural blood cell variation in the population also influence whether or not a JAK2 somatic mutation will go on to cause MPN. The team also found individuals with an inherited risk of having a higher blood cell count could display MPN features without cancer-driving mutations.

First author Jing Guo 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.”

Co-senior author Professor Nicole Soranzo added: “There has been increasing realisation that human diseases have complex causes involving a combination of common and rare inherited genetic variants with different severity.

“Previously, we have 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.”


Guo J, Walter K, Quiros PM, Gu M, Baxter EJ, Danesh J, Di Angelantonio E, Roberts D, Guglielmelli P, Harrison CN, Godfrey AL, Green AR, Vassiliou GS, Vuckovic D, Nangalia J, Soranzo N. (2024) “Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms.” Nature Genetics, doi:10.1038/s41588-023-01638-x

Link: https://www.nature.com/articles/s41588-023-01638-x


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