A study published online in Nature Genetics reveals that scientists at the Washington University School of Medicine in St. Louis have uncovered a critical genetic mutation in some patients with myelodysplastic syndromes, which is are blood cancers that can progress to a fatal form of leukemia.

The researchers also established that patients with the mutation are evidently more likely to develop acute leukemia. Even though this finding needs to be confirmed in additional patients, the study could pave the way for genetic tests in the future that can diagnose the disorder more precisely and predict the course of the disease.

Researchers discovered the mutation in a gene known as U2AF1, whilst they were sequencing the entire genome of a 65-year old male with myelodysplastic syndrome that had progressed to leukemia. The researchers compared the mutation with the genome of his tumor cells, and subsequently also identified the genetic error in other patients with myelodysplastic syndromes, which indicates the significance of the mutation.

Senior author and hematologist/oncologist Matthew Walter, MD, assistant professor of medicine says:

“The mutation in this gene was not on anyone’s radar screen. In many cases, the diagnosis of myelodysplastic syndromes is unclear because there isn’t a straightforward diagnostic test. By understanding at the genetic level what is contributing to this disease, we hope to eventually improve the diagnosis and treatment of this disorder.”

Approximately 28,000 Americans above the age of 60 years are annually diagnosed with myelodysplastic syndrome, a hard-to-treat family of blood cancers that occur when blood cells in the bone marrow do not mature properly. The disease is incurable although drugs exist for treatment.

The disorder progresses to a form of acute myeloid leukemia in about 30% of cases, which usually ends in mortality, given that chemotherapy drugs are ineffective in these patients.

Doctors are currently evaluating what likelihood patients with myelodysplastic syndrome have in developing leukemia. They examine the tumor’s chromosomes to establish to which extent they broke apart and rearranged themselves, which indicates the severity of the disease.

First author Timothy Graubert, MD, associate professor of medicine, who specializes in treating patients with myelodysplastic syndromes explains:

“There are chromosomal patterns that indicate high risk and low risk, but the current methods to determine prognosis aren’t perfect.”

The researchers identified three patients with the U2AF1 mutation through whole-genome sequencing. They sequenced another 150 patients with myelodysplastic syndromes and identified 13 patients or nearly 9% with the mutation. They concluded that the mutations in each patient occurred during the development of myelodysplastic syndromes, seeing that they were not present in normal cells. Those patients who had a U2AF1 gene mutation were nearly three times more likely to develop leukemia compared with those who did not.

The researchers observed that in 15.2% of patients with mutation, the disorder progressed to leukemia compared with 5.8% of those without.

According to the findings, the most common mutation resulted in a single letter change in the DNA at a precise location in the U2AF1 gene. The researchers discovered, that the serine (a form of amino acid) in most mutation-positive patients tended be substituted by phenylalanine or tyrosine. They say that the mutation alone does not cause myelodysplastic syndromes but seems to be an early event in the course of the disease.

The U2AF1 gene usually makes a protein involved in splicing RNA, a sister molecule of DNA, which carries the instructions for building proteins.

Splicing brings together different sections of RNA that are needed to make a protein, whilst those sections that are not required are discarded. Even though the mutated version of the gene continues to produce a protein its splicing activity is changed, suggesting that it could be significant for the development of some cancers.

The new study adds to several new findings regarding the genetic basis of myelodysplastic syndromes. This study, alongside earlier studies published in Nature and the New England Journal of Medicine, have detected mutations in eight genes in patients with this disorder, which were involved in RNA splicing.

Grauber comments:

“Together, these findings are a real game-changer. A mutation in any one of these eight genes occurs in up to 50 percent of patients with myelodysplastic syndromes. Because these changes are so common, we think there are likely to be implications for improving the diagnosis of the disorder and finding new therapeutic options.”

Scientists at the Washington University School of Medicine and the university’s Genome Institute, including Richard Wilson, PhD; Elaine Mardis, PhD; Timothy Ley, MD; and Li Ding, PhD, all co-authors of the study, pioneered whole-genome sequencing for cancer. The new research is based on previous work to discover novel mutations in cancer by examining a patient’s entire genome.

The research was supported by the National Institutes of Health (NIH) and a Howard Hughes Medical Institute Physician-Scientist Early Career Award, and partly funded by a federal stimulus grant.

Written by Petra Rattue