It is almost inevitable that we will develop genetic mutations
associated with leukaemia as we age, according to new research.
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 of 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," said Dr Naomi Park, also 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, 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."
The paper, Leukemia-associated somatic mutations drive distinct patterns of
age-related clonal hemopoiesis, is published in Cell
Reports.