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

WISMUT 生物库德国铀矿工人的白血病前期遗传变化和克隆造血

• 批准号: 433083317
• 负责人: Professor Dr. Tamam Bakchoul
• 金额: --
• 依托单位: Institut für Pathologie und Neuropathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/433083317?language=en
• 关键词: Preleukemic; genetic; changes; clonal; hematopoiesis

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.

血液学肿瘤的特征性复发突变存在于10%的>65岁的健康老年个体的白细胞中，称为不确定潜能的克隆性造血（CHIP）。CHIP的存在与髓系肿瘤的风险增加相关，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，暴露于电离辐射与髓系白血病和骨髓增生异常综合征的风险增加有关，但负责的机制仍不清楚，辐射相关白血病风险的生物标志物非常可取。鉴于CHIP在老年人中的高频率，对辐射暴露个体的白血病前遗传改变的调查可能提供一种替代方法来调查电离辐射和白血病风险的影响。因此，在两步方法中，我们将使用来自德国铀矿生物库（GUMB）的400名老年铀矿工人的白细胞DNA，这是一个独特的职业辐射暴露个体的生物材料收集，具有详细的剂量测定和健康数据，以及400名匹配的健康，非暴露对照，以确定与辐射暴露和白血病风险潜在相关的体细胞遗传改变。首先，80个GUMB样本（高暴露和低暴露各40个）和80个对照将进行WGS，以识别全局变化和潜在的候选基因/区域。将使用靶向定制NGS组对剩余的320个GUMB和匹配的对照样品进行这些候选物的验证，所述靶向定制NGS组包括由WGS鉴定的候选基因以及在CHIP中反复受影响的基因。两个队列的比较生物信息学分析将揭示辐射暴露是否与CHIP频率增加或其他适合作为潜在辐射生物标志物的复发性遗传变化相关，并可能进一步了解白血病发生的遗传基础。