Two teams of researchers independently discovered a subset of somatic mutations in blood samples that appears to significantly increase an individual's risk of developing a hematologic cancer later in life.

Two teams of researchers independently discovered that somatic mutations in the DNA of peripheral blood cells associate with an individual's risk of developing hematologic cancers later in life.

In both studies, researchers conducted whole-exome sequencing of DNA in blood samples taken from individuals not known to have cancer or blood disorders. They found that more than 10% of individuals over age 70 carried somatic mutations common in hematologic cancers, resulting in an overall 5% risk of a cancer diagnosis within 5 to 10 years. Most of the mutations occurred in three genes recognized as drivers of blood cancers: DNMT3A, ASXL1, and TET2.

One study, led by Siddhartha Jaiswal, MD, PhD, clinical fellow at Massachusetts General Hospital in Boston, analyzed more than 17,000 DNA samples from patients enrolled in type 2 diabetes and heart disease studies to determine whether it is possible to detect early somatic mutations that may initiate hematologic cancers (N Engl J Med 2014;371:2488–98).

DNMT3A, ASXL1, and TET2 seem to be initiators of malignant progression,” says Jaiswal, who presented his team's findings last month at the American Society of Hematology Annual Meeting in San Francisco. The findings corroborate earlier studies in mouse models, he says, which show that loss of TET2 or DNMT3A results in an increase in blood stem cells and a selective growth advantage.

After a median follow-up period of 8 years, Jaiswal's group assessed DNA samples and found that carrying a mutation was also associated with all-cause mortality.

“We found that individuals with mutations were about 40% more likely to die in the follow-up period, and the causes extended beyond cancer to cardiovascular disease,” says Jaiswal. “When we looked deeper, we found that people with the mutations were 2 to 2.5 times more likely to have cardiovascular events than people without the mutations.”

A second study, led by Giulio Genovese, PhD, a computational biologist at the Broad Institute of MIT and Harvard in Cambridge, MA, set out to examine somatic mutations that may contribute to risk for schizophrenia using a database of DNA samples from more than 12,000 people, about half of whom had schizophrenia or bipolar disorder; the rest served as controls (N Engl J Med 2014;371:2477–87).

After realizing that somatic mutations were concentrated in cancer genes, Genovese's team examined patients' medical histories and found that those with the mutations had a higher risk of blood cancer than healthy controls. They detected the somatic mutations in 42% of study participants who were diagnosed with a blood cancer more than 6 months after the DNA samples were taken.

Researchers emphasize that it is premature to screen otherwise healthy people for premalignant somatic mutations, because the absolute risk of progressing to cancer is very low, and there is no way to prevent the development of cancer. However, the studies may have immediate implications for cancer diagnostics.

“When you suspect someone might have a malignancy like myelodysplastic syndrome, screening for these mutations can have negative predictive value,” says Jaiswal. “However, the presence of a mutation alone is not sufficient to make a cancer diagnosis in the absence of other clinical data. If there is no detectable mutation, it's much more likely that the person does not actually have a malignancy.”

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