The evoutionary dynamics and fitness landscape of clonal hematopoiesis

The Blundell Lab has today published its first paper in Science. The paper, The evolutionary dynamics and fitness landscape of clonal hematopoiesis, addresses a key question in the field of early cancer detection, namely which specific mutations enable cells to expand most rapidly, and thus might confer the highest risk of cancer?

The group, along with colleagues at Stanford University, developed a method that is able to estimate the growth rates of mutations that expand in healthy tissues, without needing to use longitudinal data. To do this they applied evolutionary theory to mutation size estimates in blood sequencing data collected from ~50,000 individuals to quantify the growth potential (or ‘fitness effect’) of specific mutations at single nucleotide resolution. This enabled them to build a league table of the ‘fittest’ and therefore potentially most pathogenic mutations in blood. They were also able to quantify the distribution of fitness effects within genes and therefore what proportion of mutations within a gene are potentially high risk. This exciting development, combined with future studies that longitudinally track individuals over time, will shed light on how mutations drive the development of cancer and will help to accelerate the development of risk predictors.

Lead author Dr Caroline J. Watson commented "Knowing whether specific mutations are high-risk or clinically insignificant will be key in the future of personalised cancer risk stratification. Our framework provides a rational basis for quantifying the growth potential of mutations and, in combination with studies that can track these mutations and their outcomes over time, will be an important step towards this goal.”

Senior author Dr Jamie R. Blundell commented “Blood provides an ideal model system for understanding the earliest stages in cancer development. The scale and resolution of the genomic data in blood is unparalleled, and, combined with quantitative methods borrowed from evolutionary biology has enabled us to identify the variants most likely to pose a high risk of a future blood cancer developing.”

Caroline has also created a video abstract which may be viewed on YouTube here.

27 Mar 2020