Somatic mutations linked to future disease risk

Burgess, Darren J.

doi:10.1038/nrg3889

Research Highlight
Published: 23 December 2014

Human genetics

Somatic mutations linked to future disease risk

Darren J. Burgess

Nature Reviews Genetics volume 16, page 69 (2015)Cite this article

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In the largest studies of their type to date, Jaiswal et al. and Genovese et al. carried out whole-exome sequencing on blood samples from 17,182 and 12,380 people, respectively, who had no clinically apparent haematological pathologies. Somatically acquired driver mutations were identified by two complementary approaches. Jaiswal et al. focused on scanning known haematological malignancy driver genes for pathogenic mutations. By contrast, Genovese et al. looked broadly for somatic variants that were at sufficient allelic frequency in the blood (∼10–20%) to suggest that they provided a proliferative advantage to haematopoietic cells to result in their clonal expansion, but that were still below the 50% frequency expected from a heterozygous germline variant.

Both teams found that the most frequent mutations were in three chromatin-related genes: DNA methyltransferase 3A (DNMT3A), TET methylcytosine dioxygenase 2 (TET2, which is involved in DNA demethylation) and the Polycomb group gene ASXL1, which maintains repressive chromatin. Interestingly, the mutation frequencies increased with age — mutations in any of these genes were found in ≤1% of people under 50 years of age, but in ≥10% of people aged more than 65 years.

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References

Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. http://dx.doi.org/10.1056/NEJMoa1408617 (2014)
Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. http://dx.doi.org/10.1056/NEJMoa1409405 (2014)

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