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Findings pave way for new lines of cancer research focused on detection and prevention

Researchers from the Broad Institute of MIT and Harvard, Harvard Medical School, and Harvard-affiliated hospitals have uncovered an easily detectable, “pre-malignant” state in the blood that significantly increases the likelihood that an individual will go on to develop blood cancers such as leukemia, lymphoma, or myelodysplastic syndrome. The discovery, which was made independently by two research teams affiliated with the Broad and partner institutions, opens new avenues for research aimed at early detection and prevention of blood cancer. Findings from both teams appear in the New England Journal of Medicine.

Most genetic research on cancer to date has focused on studying the genomes of advanced cancers, to identify the genes that are mutated in various cancer types. These two new studies instead looked at somatic mutations – mutations that cells acquire over time as they replicate and regenerate within the body – in DNA samples collected from the blood of individuals not known to have cancer or blood disorders.

Taking two very different approaches, the teams found that a surprising percentage of those sampled had acquired a subset – some but not all – of the somatic mutations that are present in blood cancers. These individuals were more than ten times more likely to go on to develop blood cancer in subsequent years than those in whom such mutations were not detected.

The “pre-malignant” state identified by the studies becomes more common with age; it is rare in those under the age of 40, but appears with increasing frequency with each decade of life that passes, ultimately appearing in more than 10% of those over the age of 70. Carriers of the mutations are at an overall 5% risk of developing some form of blood cancer within five years. This “pre-malignant” stage can be detected simply by sequencing DNA from blood.

“People often think about disease in black and white – that there’s ‘healthy’ and there’s ‘disease’ – but in reality most disease develops gradually over months or years. These findings give us a window on these early stages in the development of blood cancer,” said Steven McCarroll, senior author of one of the papers. McCarroll is an assistant professor of genetics at Harvard Medical School and director of genetics at the Broad’s Stanley Center for Psychiatric Research. Benjamin Ebert, an associate member of the Broad and associate professor at Harvard Medical School and Brigham and Women’s Hospital, is the senior author of the other paper.

The mutations identified by both studies are thought to originate in blood stem cells, and confer a growth-promoting advantage to the mutated cell and all of its “clones” – cells that derive from that original stem cell during the normal course of cell division. These cells then reproduce at an accelerated rate until they account for a large fraction of the cells in a person’s blood. The researchers believe these early mutations lie in wait for follow-on, “cooperating” mutations that, when they occur in the same cells as the earlier mutations, drive the cells toward cancer. The majority of mutations occurred in just three genes; DNMT3A, TET2, and ASXL1.