Abstract
Clonal hematopoiesis (CH) – age-related expansion of mutated hematopoietic clones – can differ in frequency and cellular fitness. Descriptive studies have identified a spectrum of events (coding mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-existence of different CH events raises key questions as to their origin, selection, and impact. Here, we report analyses of sequence and genotype array data in up to 482,378 individuals from UK Biobank, demonstrating shared genetic architecture across different types of CH. These data highlighted evidence for a cellular evolutionary trade-off between different forms of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. Furthermore, we observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Individuals carrying these overlapping somatic mutations had a large increase in risk of future hematological malignancy (HR=17.31, 95% CI=9.80-30.58, P=8.94×10−23), which is significantly elevated compared to individuals with non-overlapping CHIP and autosomal mCAs (Pheterogeneity=8.83×10−3). Finally, we leverage the shared genetic architecture of these CH traits to identify 15 novel loci associated with blood cancer risk.
Competing Interest Statement
V.G.S. serves as an advisor to and/or has equity in Branch Biosciences, Ensoma, Novartis, Forma, and Cellarity, all unrelated to the present work. All other authors declare no relevant competing interests.
Footnotes
↵^ These authors jointly supervised this work
We have performed several new analyses including: (1) We have added time to event analyses, which demonstrates that individuals with overlapping CHIP and mCAs are at substantially elevated hazard of acquiring hematologic malignancies (17-fold increased risk) relative to unaffected individuals, as well as individuals with either CHIP or mCAs. (2) We have incorporated new mosaic Y chromosome loss (LOY) exome analyses to demonstrate that variation in well-established CHIP genes such as TET2, ASXL1 and DNMT3A is protective for LOY. This reinforces our previous phenotypic analyses and suggests a cellular evolutionary trade-off between different forms of clonal hematopoiesis. (3) Finally, we leverage all of these data to identify 15 novel loci associated with blood-based cancer (MPN).