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

血液肿瘤特有的反复突变存在于10%的65岁健康老年人的白细胞中，称为克隆性造血不确定潜能(CHIP)。CHIP的存在与髓系肿瘤风险的增加有关，突变的类型、数量和等位基因频率决定了过度风险的程度。与CHIP一样，暴露在电离辐射下与髓系白血病和骨髓增生异常综合征的风险增加有关，但其责任机制仍不清楚，辐射暴露相关白血病风险的生物标记物是非常可取的。鉴于CHIP在老年人中的频率很高，研究辐射暴露个人的白血病前基因变化可能为研究电离辐射的影响和白血病风险提供一种替代方法。因此，在一个分两步走的方法中，我们将使用来自德国铀矿生物库(Gumb)的400名老年铀矿工的白细胞DNA，Gumb是一个独特的生物材料集合，收集了具有详细剂量测定和健康数据的职业辐射暴露个人，以及400名匹配的健康非暴露对照，以确定可能与辐射暴露和白血病风险相关的体细胞基因改变。首先，80个Gumb样本(高暴露和低暴露各40个)和80个对照将接受WGS，以确定全球变化和潜在的候选基因/区域。这些候选基因的验证将分别在剩余的320个Gumb和匹配的对照样本上进行，使用一个有针对性的定制NGS小组，包括WGS确定的候选基因以及芯片中反复受到影响的基因。对这两个队列的比较生物信息学分析将揭示辐射暴露是否与芯片频率增加或适合作为潜在辐射生物标记物的其他反复发生的遗传变化有关，并可能进一步深入了解白血病发生的遗传基础。

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.