Preleukemic genetic changes and clonal hematopoiesis in German Uranium miners of the WISMUT Biobank

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Recurrent mutations characteristic for hematological neoplasms are present in leukocytes of 10% of healthy elderly individuals >65 years, termed clonal hematopoiesis of indeterminate potential (CHIP). The presence of CHIP is associated with an increased risk for myeloid neoplasms, with the type, number and allele frequency of mutations determining the extent of excess risk. Like CHIP, exposure to ionizing radiation is associated with an increased risk for myeloid leukemia and myelodysplastic syndromes, but the responsible mechanisms are still unclear, and biomarkers for radiation exposure-associated leukemia risk are highly desirable. Given the high frequency of CHIP in the elderly, the investigation of pre-leukemic genetic alterations in radiation-exposed individuals might provide an alternative approach to investigate the impact of ionizing radiation and leukemia risk. In a two-step approach, we will therefore use leukocyte DNA from 400 elderly uranium miners from the German Uranium Miner Biobank (GUMB), a unique biomaterial collection of occupationally radiation-exposed individuals with detailed dosimetry and health data, and 400 matched healthy, non-exposed controls to identify somatic genetic alterations potentially associated with radiation exposure and leukemia risk. First, 80 GUMB samples (40 each with high and low exposure) and 80 controls will undergo WGS to identify global changes and potential candidate genes/regions. Validation of these candidates will be performed on the remaining 320 GUMB and matched control samples each, using a targeted custom NGS panel including the candidate genes identified by WGS, as well as genes recurrently affected in CHIP. Comparative bioinformatic analysis of the two cohorts will reveal whether radiation exposure is associated with an increased CHIP frequency or other recurrent genetic changes suitable as potential radiation biomarker and might provide further insight into the genetic basis of leukemogenesis.