Identification of a pre-cancerous state in the blood

US researchers have uncovered a ‘pre-malignant’ state in the blood that significantly increases the likelihood that an individual will develop blood cancers such as leukaemia, lymphoma or myelodysplastic syndrome. The discovery was made independently by two research teams from the Broad Institute of MIT and Harvard, Harvard Medical School and Harvard-affiliated hospitals, who published their work in the New England Journal of Medicine.

The studies 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 of the somatic mutations that are present in blood cancers. These individuals were more than 10 times more likely to go on to develop blood cancer in subsequent years than those in whom such mutations were not detected.

Benjamin Ebert’s team had hypothesised that, since blood cancers increase with age, it might be possible to detect early somatic mutations that could be initiating the disease process, and that these mutations also might increase with age. They looked at 160 genes known to be recurrently mutated in blood malignancies, using genetic data derived from approximately 17,000 blood samples originally obtained for studies on the genetics of type 2 diabetes.

Somatic mutations in these genes did indeed increase the likelihood of developing cancer and saw a clear association between age and the frequency of these mutations. Men were slightly more likely to have mutations than women, and Hispanics were slightly less likely to have mutations than other groups. The team also found an association between the presence of this pre-malignant state and risk of overall mortality independent of cancer - with a higher risk of type 2 diabetes, coronary heart disease and ischemic stroke - but additional research will be needed to determine the nature of these associations.

Steven McCarroll’s team were also looking at somatic mutations, but were initially interested in determining whether such mutations contributed to risk for schizophrenia. The team studied roughly 12,000 DNA samples drawn from the blood of patients with schizophrenia and bipolar disorder, as well as healthy controls, searching across the whole genome at all of the protein-coding genes for patterns in somatic mutations. They found that the somatic mutations were concentrated in a handful of genes, which turned out to be cancer genes.

The team then used electronic medical records to follow the patients’ subsequent medical histories, finding that the subjects with these acquired mutations had a 13-times elevated risk of blood cancer. They conducted follow-up analyses on tumour samples from two patients who had progressed from this pre-malignant state to cancer, which revealed that the cancer had indeed developed from the same cells that had harboured the ‘initiating’ mutations years earlier.

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 three genes: DNMT3A, TET2 and ASXL1.

“Cancer is the end stage of the process,” said Siddhartha Jaiswal, the first author on Ebert’s paper. “By the time a cancer has become clinically detectable, it has accumulated several mutations that have evolved over many years. What we are primarily detecting here is an early, pre-malignant stage in which the cells have acquired just one initiating mutation.”

The pre-malignant state was found to become more common with age, increasing in frequency with every decade over the age of 40 and ultimately appearing in more than 10% of those over the age of 70. According to McCarroll, the results are indicative of the fact that “most disease develops gradually over months or years” and provide “a window on these early stages in the development of blood cancer”.

Carriers of the mutations are at an overall 5% risk of developing some form of blood cancer within five years, but while there are no current treatments that would address this condition, the results do open the door to new directions for blood cancer research.

“The results demonstrate a way to identify high-risk cohorts - people who are at much higher than average risk of progressing to cancer - which could be a population for clinical trials of future prevention strategies,” McCarroll said. “The abundance of these mutated cells could also serve as a biomarker - like LDL cholesterol is for cardiovascular disease - to test the effects of potential prevention therapies in clinical trials.”

Ebert added, “A new focus of investigation will now be to develop interventions that might decrease the likelihood that individuals with these mutations will go on to develop overt malignancies, or therapeutic strategies to decrease mortality from other conditions that may be instigated by these mutations.”

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