Scientists have uncovered a critical genetic mutation in some patients with myelodysplastic syndromes – a group of blood cancers that can progress to a fatal form of leukemia. The research team at Washington University School of Medicine in St. Louis also found evidence that patients with the mutation are more likely to develop acute leukemia.

While this finding needs to be confirmed in additional patients, the study raises the prospect that a genetic test could one day more accurately diagnose the disorder and predict the course of the disease. The research is available online in Nature Genetics.

The scientists discovered the mutation in a gene known as U2AF1 when they sequenced the entire genome of a 65-year old man with myelodys plastic syndrome that had progressed to leukemia and compared it with the genome of his tumor cells.

They also found the genetic error in other patients with myelodysplastic syndromes, an indication of the mutation’s significance.

The mutation in this gene was not on anyone’s radar screen.” Matthew Walter MD Assistant Professor “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,” he explained. Myelodysplastic syndromes are a difficult-to-treat family of blood cancers that occur when blood cells in the bone marrow don’t mature properly. About 28,000 Americans are diagnosed with the disorder each year, most of them over age 60.

Drugs are available to treat the disease, but none can cure it. In about 30 percent of cases, the disorder progresses to a form of acute myeloid leukemia that usually is fatal because chemotherapy drugs are not effective in these patients. Doctors currently assess the likelihood that a patient with myelodysplastic syndrome will develop leukemia by looking at the chromosomes in the tumor cells to determine the extent to which they have broken apart and rearranged themselves, an indicator of the severity of the disease.

There are chromosomal patterns that indicate high risk and low risk, but the current methods to determine prognosis aren’t perfect.” Timothy Graubert MD Associate Professor Medicine Patients were almost three times as likely to develop leukemia if they had a mutation in the U2AF1 gene. The disorder progressed to leukemia in 15.2 percent of patients with the mutation, compared with 5.8 percent of those without the genetic error. The most common mutation results in a single letter change in the DNA at a precise location in the U2AF1 gene.

Patients with the genetic error were most likely to have the amino acids phenylalanine or tyrosine substituted for a serine. The researchers say that the mutation by itself does not cause myelodysplastic syndromes but appears to be an early event in the course of the disease.

The new research, funded in part by a federal stimulus grant, adds to a flurry of new findings about the genetic basis of myelodysplastic syndromes. Recent studies in Nature and the New England Journal of Medicine, along with the current study, have identified mutations in a total of eight genes involved in RNA splicing in patients with the disorder.

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