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Early Genetic Changes Distinguish Individuals at Increased Risk of Acute Myeloid Leukemia

NEW YORK (GenomeWeb) – Early genetic changes can be used to identify individuals who are at an increased risk of developing acute myeloid leukemia, according to a new study.

More than 19,500 people will be diagnosed with AML this year in the US, according to the National Cancer Institute. Patients typically exhibit few symptoms before the disease's abrupt onset, but an international team of researchers sought to identify those at increased risk.

Using data collected by the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which began in 1992, the researchers compared blood samples from people who went on to develop AML and those who did not. As they reported in Nature today, the researchers pinpointed genetic alterations that distinguished those who later developed AML, which they bundled into a predictive test for the disease.

"Acute myeloid leukemia often appears very suddenly in patients, so we were surprised to discover that its origins are generally detectable more than five years before the disease develops," co-first author Grace Collord from the Wellcome Sanger Institute and University of Cambridge, said in a statement. "This provides proof­of­principle that it may be possible to develop tests to identify people at a high risk of developing AML."

Before developing AML, patients first accumulate somatic mutations within pre-leukemic hematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion. However, similar mutations also accumulate within the HSPCs of healthy individuals as they age, in a benign process dubbed age-related clonal hematopoiesis (ARCH). Through deep sequencing, the researchers sought to tease out genetic changes that differ between the processes.

Collord and her colleagues performed deep error-corrected targeted sequencing — focusing on AML-associated genes — on peripheral blood samples from 95 pre-AML cases and 414 age- and gender-matched controls. The pre-AML samples were obtained an average 6.3 years before diagnosis. The researchers validated their findings in an additional cohort of 29 cases and 262 controls.

Overall, they found that pre-AML cases harbored more mutations and that more of their blood cells were affected by the mutations. In the combined discovery and validation cohorts, 73.4 percent of the pre-AML cases had ARCH, while 36.7 percent of the controls did. The median number of ARCH-related mutations increased with age and was higher in the pre-AML group.

In both groups, DNMTA3A and TET2 were commonly mutated. The researchers noted that they did not observe any canonical NPM2 mutations or FLT3-internal tandem duplication mutations, which they said was consistent with these mutations cropping up late in disease development.

They also ranked the mutations they uncovered based on how often they were reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Recurrent cancer mutations, they found, were more common among the pre-AML cases than among controls. In all, they said this indicates that there are differences in the mutational landscape of ARCH and pre-AML and that AML progression occurs over the course of a few years before late mutations lead to malignant transformation.

They also found that mutations in some genes conferred a greater risk of developing AML than others. For instance, mutations in DNMTA3A and TET2 confer a low risk of AML progression, while mutations in TP53 and U2F1 gave a much higher risk of disease progression, the researchers said.

Using that information, they developed a predictive test for AML into which they then folded additional data from patients' electronic health records. This test could predict AML six to 12 months before diagnosis with a sensitivity of 25.7 percent and a specificity of 98.2 percent.

However, the researchers also noted that as AML incidence rates are low, predictive tests need to be highly accurate to avoid false-positive results. Still, they said their findings are a proof-of-principle that ARCH and pre-AML can be distinguished potentially years before disease onset.

"We hope to build on these findings to develop robust screening tests for identifying those at risk and drive research into how to prevent or stall progression towards AML," co-senior author George Vassiliou from the Sanger Institute said in a statement.