Genes driving abnormal growth of mutated blood cells identified

Somatic mutations in 17 genes have been associated with the aberrant growth and maturation of blood cells, providing new insights into causes of cancer and heart disease.

A team of UK- and USA-based researchers retrospectively analysed DNA sequencing data stored in the UK Biobank from over 200,000 individuals to identify genes involved in clonal haematopoiesis. Clonal haematopoiesis is a process whereby hematopoietic stem cells gain age-related mutations which confer a survival advantage, thus overgrowing and outnumbering healthy blood cells. Somatic mutations in 17 new genes were identified as drivers of clonal haematopoiesis, which is itself associated with the development of certain cancers (ie leukaemia) and cardiovascular mortality.   

Co-first author Dr Michael Spencer Chapman of the Wellcome Sanger Institute, said 'While existing genetic tests have been valuable for early disease detection, our findings suggest there are opportunities to improve them further… By incorporating these 17 additional genes linked to clonal haematopoiesis, we can enhance genetic testing methods to better identify risks of associated blood cancers and cardiovascular diseases.'

When the team included the 17 genes (ZBTB33, ZNF318, ZNF234, SPRED2, SH2B3, SRCAP, SIK3, SRSF1, CHEK2, CCDC115, CCL22, BAX, YLPM1, MYD88, MTA2, MAGEC3 and IGLL5) in their analysis of UK BioBank health records, the prevalence of clonal haematopoiesis was shown to be 18 percent higher than previously expected. Furthermore, individuals with mutations in these genes were more likely to develop lymphoid malignancies, infections, pneumonia or leukaemia, underscoring their clinical relevance. As summarised by co-first author Nick Bernstein, formerly of Calico Life Sciences: 'While interventions based on this research are still a long way off, it opens up possibilities for future treatments across a wide range of diseases.'

In a separate study published in 2021 in Blood Cancer Discovery, four of the genes highlighted (SRCAP and YLPM1, ZBTB33 and ZNF318) were corroborated as clonal haematopoiesis drivers in an analysis of over 45,000 samples from the Exome Aggregation Consortium (ExAC) database. These data build upon the ~70 genes previously implicated in the development of clonal haematopoiesis and indicate that more remain to be discovered, leading to a greater understanding of the causes of clonal haematopoiesis and related health conditions.

The study was published in Nature Genetics.