Genetic alterations driving acute myeloid leukaemia can emerge before a patient turns twenty, more than half a century before clinical diagnosis.
Researchers at the University of Cambridge and University College London studied blood specimens collected over decades. They tracked the evolutionary history of the aggressive blood cancer in an observational study published in Nature.
The initial genetic mutation occurred during youth or childhood in two-thirds of analysed cases.
Acute myeloid leukaemia affects roughly 2,700 people in the United Kingdom annually. Only about one in six patients survive five years past diagnosis.
Many older adults carry blood cells with leukaemia-associated mutations. This condition is known as clonal haematopoiesis, but only a small fraction develop the full malignancy.
The team examined archived blood specimens gathered through the UK Collaborative Trial of Ovarian Cancer Screening to uncover biological triggers.
That trial enrolled 202,638 post-menopausal women aged 50 to 74 across England, Wales, and Northern Ireland between 2001 and 2005.
At enrolment, 50,640 participants joined a multimodal screening arm involving annual blood serum donations for up to 11 years, ending on December 31, 2011.
The investigation focused on 47 women who later developed acute myeloid leukaemia at a median age of 72. Serial samples matched by timepoint came from 47 participants who remained free of blood cancer.
One control participant was subsequently excluded after developing myelodysplastic syndrome.
Researchers used ultra-sensitive DNA sequencing and mathematical modelling. They treated longitudinal blood specimens collected up to 15 years before diagnosis as a molecular fossil record.
Mutant blood cells underwent decades of extremely slow proliferation after the initial mutation acquired before age 20. They took years to double in number.
Investigators identified a somatic sweep in at least one-third of the leukaemia cases. A single clone expanded to dominate circulating blood years before diagnosis.
No such somatic sweeps appeared in the control cohort of cancer-free women.
UK Biobank records validated the link between somatic sweeps and disease risk.
Clonal dominance is a warning sign. Standard genetic sequencing frequently misses it by classifying the variants as inherited germline traits.
Dr Caroline Watson said that clinical presentation contrasts with evolutionary buildup. She is lead author of the study and an Honorary Consultant Haematologist at the Cambridge Clonal Haematopoiesis Clinic at Addenbrooke’s Hospital.
“At Addenbrooke’s, specialists already monitor individuals carrying mutated blood cells that elevate leukaemia risk,” Watson said.
Professor Usha Menon said the bioresource established during the ovarian cancer screening initiative was valuable. She is from University College London and led the trial program.