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Deep Sequencing Study Finds Leukemia-linked Mutations Common in Aging

NEW YORK (GenomeWeb) – A deep-sequencing study has found that mutations associated with leukemia are more common than previously thought among elderly people.

Researchers from the Wellcome Trust Sanger Institute and elsewhere performed targeted ultra-deep sequencing at certain mutational hotspots on more than 4,200 people between the ages of 17 and 98. While some leukemia-linked mutations were found in people of all ages, other mutations were only present in people older than 70 years of age, they reported today in Cell Reports.

"Ultra-deep sequencing has allowed us to see the very beginnings of cancer," said senior author George Vassiliou from the Sanger and Cambridge University Hospitals NHS Trust in a statement. "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."

Vassiliou and his colleagues focused on 15 loci that are frequently mutated in myeloid malignancies in blood DNA samples from 4,219 individuals using a combination of barcoded multiplex PCR and next-generation sequencing. The genes they examined included DNMT3A and JAK2, among others.

From this, they examined the occurrence of age-related clonal hemopoiesis as well as of certain mutations in their cohort.

They identified clonal hemopoiesis in less than 1 percent of participants under the age of 60, a figure that rose to 19.5 percent of those over the age of 90. This, the researchers said, indicated that clonal hemopoiesis is more common than previously thought, and they suggested that it is "an almost inevitable consequence of advanced aging."

The most common mutation Vassiliou and his colleagues found affected DNMT3A R882, which was present in 0.2 percent of the individuals in the 17-years to 29-years-old age bracket, but was present in 3.1 percent of the people in the 80-years-old to 89-years-old age bracket. JAK2 V617F mutations were similarly present among individuals of all ages, but more common among older people.

This pattern, the researchers said, was consistent with the cumulative likelihood of these mutations being randomly acquired over time.

However, other mutations — especially ones affecting spliceosome genes — were only present in people over the age of 70. The investigators found that 1.8 percent of people between the ages of 70 and 79 had RSF2 P95, SF3B1 K666, or SF3B1 K700 mutations, while 8.3 percent of those over the age of 90 had those mutations.

This rise in spliceosome gene mutations around 70 years of age mirrors the increase of myelodysplatic syndromes at that age, the researchers added, and they suggested that the presence of these mutations only in elderly people could be due to differences in pressures on clonal selection during aging.

At the same time, Vassiliou and his colleagues did not find any instances of an NPM1 mutation — a mutation that is found in some 40 percent of leukemia cases — in their cohort. This, they said, indicates that NPM1 mutations may act as gatekeepers of leukemogenesis.

"The significance of mutations in this gene is astonishingly clear from these results: it simply doesn't exist where there is no leukemia," co-first author Naomi Park from the Sanger said. "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."