That means it is almost inevitable that we will develop genetic mutations associated with leukemia as we age, according to the authors investigating the earliest stages of cancer development used an exquisitely sensitive sequencing method capable of detecting DNA mutations present in as few as 1.6 percent of blood cells, to analyze 15 locations in the genome, which are known to be altered in leukemia.
By comparing their findings with other research conducted with a lower degree of sensitivity over whole exomes, the scientists were able to conclude that the incidence of pre-leukemic cells in the general population is much higher than previously thought and increases dramatically with age.
"Leukemia results from the gradual accumulation of DNA mutations in blood stem cells, in a process that can take decades," says Dr. Thomas McKerrell, joint first author from the Wellcome Trust Sanger Institute. "Over time, the probability of these cells acquiring mutations rises. What surprised us was that we found these mutations in such a large proportion of elderly people. This study helps us understand how aging can lead to leukemia, even though the great majority of people will not live long enough to accumulate all the mutations required to develop the disease."
The pre-leukemic mutations studied appear to give a growth advantage to the cells carrying them and this starts a process in which cells with these mutations dominate blood making. As they increase in number, the likelihood that one or more of them will acquire more mutations becomes greater, something that could eventually lead to leukemia and leukemia-like disorders.
Interestingly, the study found that mutations affecting two particular genes, SF3B1 and SRSF2, appeared exclusively in people aged 70, suggesting that these mutations only give a growth benefit later in life, when there is less competition.
This finding explains why myelodysplastic syndromes, a group of leukemia-like conditions associated with these genes, appear almost exclusively in the elderly.
None of the 4,219 people studied were found to have a mutation in NPM1, the most common acute leukemia gene mutated in up to 40 percent of cases. This unexpected result suggests that mutations in NPM1 behave as gatekeepers for this cancer; once a mutation in this gene occurs in a cell with particular previously accumulated pre-leukemic mutations, the disease progresses rapidly to become leukemia.
"The significance of mutations in this gene is astonishingly clear from these results: it simply doesn't exist where there is no leukemia," says Dr Naomi Park, joint first author from the Sanger Institute. "When it is mutated in the appropriate cell, the floodgates open and leukemia is then very likely to develop. This fits with studies we've conducted in the past in which we found that the gene primes blood stem cells for leukemic transformation."
Leukemia serves as a useful model for research into the origins of cancer because blood samples are much easier to obtain than tissue samples. Each cancer begins with a single mutation in just one cell; this research allows scientists to look at how these first mutated cells accumulate to form cancer.
"Ultra-deep sequencing has allowed us to see the very beginnings of cancer," says Dr. George Vassiliou, senior author from the Sanger Institute and Cambridge University Hospitals NHS Trust. "These mutations will be harmless for the majority of people but for a few unlucky carriers they will take the body on a journey towards leukemia. We are now beginning to understand the major landmarks on that journey."
Citation: McKerrell T, Park N, et al. (2015). Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Reports. DOI: 10.1016/j.celrep.2015.02.005
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