Sanger Institute. UK: Researchers estimate that 7 in 10 over 90-year-olds harbour cells with early leukaemia mutation. It is almost inevitable that we will develop genetic mutations associated with leukaemia as we age, according to
research published today in Cell Reports. Based on a study of 4219 people without any evidence of blood
cancer, scientists estimate that up to 20 per cent of people aged 50-60 and more than 70 per cent of people over 90
have blood cells with the same gene changes as found in leukaemia.
Scientists 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
per cent of blood cells, to analyse 15 locations in the
genome, which are known to be altered in leukaemia. 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-leukaemic
cells in the general population is much higher than previously
thought and increases dramatically with age.
"Leukaemia results from the gradual accumulation of DNA mutations in blood stem cells, in a process
that can take decades," explains 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 leukaemia, even though the great majority of people will not live long enough to accumulate all the
mutations required to develop the disease."
None of the 4219 people studied were found to have a mutation in NPM1, the most common acute leukaemia gene
mutated in up to 40 per cent 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-leukaemic mutations, the disease progresses rapidly to become leukaemia.
"The significance of mutations in this gene is astonishingly clear from these results: it simply
doesn't exist where there is no leukaemia," 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 leukaemic transformation."
Leukaemia 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 leukaemia. We are now beginning to understand the major landmarks on that journey."