Biology subjects

Apostolidou, S.

Publications and source records attributed to Apostolidou, S..

2 recordsLinked to original sources

bioRxiv2025

Methylation dynamics in the decades preceding acute myeloid leukaemia

DNA methylation is emerging as a highly sensitive and specific marker of cancer initiation and progression. How these cancer-specific methylation changes are established in the decades before cancer, however, remains largely unknown. Here, we use a unique collection of longitudinal blood samples collected annually up to 15 years prior to a diagnosis of acute myeloid leukaemia to sensitively track the dynamics of DNA methylation changes at high temporal resolution. We identify thousands of differentially methylated regions (DMRs) that exhibit altered patterns of methylation up to 10 years before acute myeloid leukaemia (AML) diagnosis. Most of these DMRs are strongly associated with expanding clones carrying somatic driver mutations. We identify a subset of epigenetic driver DMRs characterised by recurrent CpG alterations that are highly shared across pre-AML cases. These are likely to reflect early epigenetic reprogramming associated with AML development. We also reveal large numbers of stochastic passenger CpGs whose differential methylation results from hitch-hiking with clonal expansions driven by somatically acquired genetic events. These passenger CpGs can be exploited for lineage tracing to discover clonal expansions driven by missing driver mutations. Our findings show widespread changes in methylation patterns during the early stages of cancer development which could be utilised for risk prediction and therapeutic intervention.

genomics↗

bioRxiv2024

Evolutionary dynamics in the decades preceding acute myeloid leukaemia

Somatic evolution in ageing tissues underlies many cancers. However, our quantitive understanding of the rules governing this pre-cancerous evolution remains incomplete. Here we exploit a unique collection of serial blood samples collected annually up to 15 years prior to diagnosis of acute myeloid leukaemia (AML) to provide a quantitative description of pre-cancerous evolutionary dynamics. Using deep duplex sequencing and evolutionary theory, we quantify the acquisition ages and fitness effects of the key driver events in AML development. The first driver mutations are typically acquired in the first few decades of life when the blood remains highly polyclonal. These early slow-growing clones subsequently acquire multiple further driver mutations which confer selective advantages up to 100-fold larger than the early drivers. These faster-growing clones harbouring multiple driver mutations can cause complete somatic sweeps of the blood decades before diagnosis, a feature strongly associated with future AML. Once established in the blood, the dynamics of driver mutations are highly predictable. Trajectories are shaped by strong clonal competition between lineages with limited evidence of other extrinsic factors playing a major role. Our data show that the clonal dynamics of blood are consistent with a set of remarkably simple evolutionary rules which strike a balance between chance and determinism.

cancer biology↗