Longitudinal characterization of mosaic chromosomal alterations identifies factors influencing clonal dynamics of leukocytes

Characterizing the variation in clonal trajectory of age-related mosaic chromosomal alterations (mCAs) in circulating leukocytes can identify etiologic factors influencing clonal expansion and hematologic malignancy risk. Here we scan whole blood-derived DNA of 56,324 participants from the Prostate, Lung, Colorectal, Ovarian Cancer Screening Study for mCAs and characterize 1746 longitudinal mCAs. Cross-sectional mCA clonal fraction only moderately correlates with clonal expansion rate, highlighting the utility of serial sampling for evaluating clonal trajectory. The strongest contributor to clonal expansion is genomic location of an mCA with participant age, smoking status, and co-occurring mCA types also modifying expansion rates. Germline susceptibility to mosaic Y or X loss is not associated with expansion rate, supporting independent mechanisms governing generation and expansion. Autosomal mCAs previously associated with hematologic malignancies have the highest rates of expansion, especially myeloid malignancy-associated mCAs, underscoring the importance of tracing mCA clonal dynamics for evaluating hematologic cancer risk.