Discovery of the role of hereditary genetic variants in rare blood cancers

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

Researchers from the Wellcome Sanger Institute, University of Cambridge and collaborators combined diverse comprehensive datasets to understand the impact of spontaneous cancer-causing mutations and inherited genetic variations on the risk of developing myeloproliferative neoplasms (MPNs). ).

The study, published today (January 17) in Natural geneticsdescribes 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 impacts current clinical predictions of disease development in individuals. Further research is needed to understand the biological mechanisms behind how these inherited genetic variants influence the risks of developing a rare blood cancer. In the future, this knowledge could facilitate the development of drugs and interventions that reduce disease risk.

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

In the population, there is a large natural variation between individuals’ blood cells, which can affect the amount of blood cells a person has and their particular characteristics. Indeed, several different genes can influence the characteristics of an individual’s blood cells. In routine blood tests, researchers take known information about these genes and analyze the variation to give a genetic risk score, which is how likely an individual is to develop a disease during their lifetime.

MPNs have been associated with random somatic mutations in certain genes, notably 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 develop MPN.

While previous studies have identified more than a dozen associated inherited genetic variants that increase the risk of MPN, these studies do not adequately explain why most individuals in the population do not develop MPN.

This new study, carried out by the Wellcome Sanger Institute and collaborators, combined information on known MPN somatic mutations, inherited genetic variants, and genetic risk scores of individuals with MPN.

They found that inherited variants that cause natural blood cell variation in the population also impact whether a somatic JAK2 mutation will cause MPN. They also found that individuals with a hereditary risk of having higher blood cell counts could exhibit MPN characteristics in the absence of cancer mutations, thereby mimicking the disease.

Dr Jing Guo, first author from the Wellcome Sanger Institute and the University of Cambridge, said: “Our large-scale statistical study helped fill knowledge gaps about how DNA variants, both hereditary as well as somatic, interact to influence the risk of complex diseases. . By combining these three different types of data sets, we were able to get a more complete picture of how these variants combine to cause blood disorders.

Professor Nicole Soranzo, co-lead author from the Wellcome Sanger Institute, University of Cambridge and Human Technopole, Italy, said: “There is a growing realization that human diseases have complex causes involving a combination of variants Previously, we have shown that variation in blood cell parameters and function exhibits complex genetic variability by highlighting thousands of genetic changes that affect different gene functions.

“Here, we show for the first time that common variants of these genes also affect blood cancers, independent of causal somatic mutations. This confirms an important new contribution of normal variability beyond complex diseases, thus contributing to our understanding of myeloproliferative neoplasms and blood cancer in general.”

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

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