The genomic landscape of clonal hematopoiesis in Japan

<jats:title>Abstract</jats:title><jats:p>Cancer and aging are widely assumed to involve similar biological trajectories in different populations, though such biology has not been systematically characterized on a population scale. Clonal hematopoiesis with acquired mutations is a pre-cancerous condition that becomes common with advancing age. Here we describe shared and population-specific patterns of genomic mutation revealed by 33,250 autosomal mosaic chromosomal alterations (mCAs) we ascertained from 179,417 Japanese participants in the BioBank Japan cohort and compared to analogous analyses of UK Biobank. In this long-lived Japanese population, mCAs were detected in more than 35.0% (s.e. 1.4%) of individuals older than 90 years, suggesting that such clones trend toward inevitability with aging. Japanese and Europeans exhibited key differences in the genomic locations of mutations in their respective hematopoietic clones, which anticipated the populations’ relative rates of CLL (more common among Europeans) and T-cell lymphoma (more common among Japanese). Multiple mutational precursors of CLL (including trisomy 12, 13q loss, and 13q CNN-LOH) were also 2-6x less common among the Japanese, suggesting that these populations differ in selective pressures on clones long before the development of clinically apparent CLL. Japanese and UK populations also exhibited very different rates of clones arising from B- and T-cell lineages, anticipating the relative rates of B- and T-cell cancers in these populations. We identified six new loci at which inherited variants predispose to mCAs that duplicate or remove inherited risk alleles, including large-effect rare variants at <jats:italic>NBN, MRE11</jats:italic>, and <jats:italic>CTU2</jats:italic> (OR=28-91). Our results motivate further exploration of the global genomic landscape of clonal hematopoiesis and cancer, and point to population-specific selective pressures on hematopoietic clones.</jats:p>