The National Center for Tumor Diseases Dresden (NCT/UCC) is a joint institution of the German Cancer Research Center (DKFZ), the University Hospital Carl Gustav Carus Dresden, Carl Gustav Carus Faculty of Medicine at TU Dresden and the Helmholtz-Zentrum Dresden-Rossendorf (HZDR).
Acute myeloid leukemia (AML) is the most common form of rapidly progressive blood cancer in adults. It is fatal within a short time if left untreated. In most cases, the cause for the occurrence of the disease have been unclear. A large-scale international study led by researchers from Newcastle University, the Icahn School of Medicine at Mount Sinai (ISMMS, New York), the University Hospital Carl Gustav Carus Dresden and the National Center for Tumor Diseases Dresden (NCT/UCC) has now shown for the first time that common inherited genetic factors increase the risk of developing AML. Until now, this kind of association was known only for very rare genetic alterations in a few AML patients and their families. "The results provide an important basis for a deeper understanding of the disease and the biological mechanisms behind it. In the future, this could open up new possibilities for preventing and better treating the disease," says Professor James M. Allan of Newcastle University. "These results are the outcome of a joint effort and were only possible thanks to many years of successful collaboration between researchers and medical professionals from ten different countries."
As part of the genome-wide association study, researchers specifically examined those sites in the approximately three billion nucleotides of the normal human DNA sequence where the genetic material differs in a single nucleotide base ("letter") in at least one percent of the population. They investigated more than 7 million of these single nucleotide polymorphisms (SNPs) and detected an alteration in the KMT5B gene that was significantly more common in the more than 4,000 AML patients analyzed than in the comparison group of approximately 10,500 healthy individuals. The researchers also identified another genetic alteration in the HLA-DQB1 gene on chromosome 6p that was substantially more frequent in patients with normal karyotype AML, the most common subtype of this disease.
"We already know that one of the discovered risk genes plays an essential role in ensuring our immune system works properly. Consequently, our results show that a strong immune system protects us from developing AML, while a less efficient immune system increases the risk of developing AML," explains Professor Friedrich Stölzel from the University Hospital Dresden.
"The very clear correlation of genetic factors and the occurrence of AML suggests that inherited genetic variants are a key factor in the development of disease," said Professor Kenan Onel of the Icahn School of Medicine at Mount Sinai. "The relevant genetic traits are inherited and can be passed on within a family."
Future studies will now investigate which biological mechanisms are triggered by the genetic changes in the body and how they contribute to the development of leukemia. On this basis, new strategies for the prevention and treatment of leukemia may be developed in the future.
Publication:
Lin, WY., Fordham, S.E., Hungate, E. et al. Genome-wide association study identifies susceptibility loci for acute myeloid leukemia. Nat Commun 12, 6233 (2021). https://doi.org/10.1038/s41467-021-26551-x
