生殖系遗传NBN 变异和易患儿童B细胞急性淋巴细胞白血病的倾向
Carolin Escherich1,2, Wenan Chen3, Yizhen Li1
1Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Research square
|July 28, 2023
概括
在儿童B细胞急性淋巴细胞白血病 (B-ALL) 中,DNA修复基因NBN的生殖系变异过多. 发现了致病变体,但携带者表现出相似的存活率,这表明对异合的NBN变体携带者进行安全的B-ALL治疗.
科学领域:
- 遗传学 是一个遗传学.
- 在瘤学瘤学.
- 分子生物学分子生物学
背景情况:
- 双基NBN突变导致尼日梅根断裂综合征,增加淋巴细胞恶性瘤的风险.
- 在白血病的发展中,异合体生殖系NBN变异的作用不太清楚.
- NBN是一种DNA损伤修复基因,对基因组稳定性至关重要.
研究的目的:
- 调查生殖线NBN变异在儿科B细胞急性淋巴细胞白血病 (B-ALL) 的频率和影响.
- 为了确定异构卵性NBN变异是否会影响患者的生存结果.
- 评估生殖线NBN变异在B-ALL.的临床影响.
主要方法:
- 在儿科B-ALL病例中对生殖线NBN编码变异进行系统查.
- 变异频率与大型非癌症控制队伍 (gnomAD) 的比较.
- 功能性测试用于评估已识别的NBN变异的致病性.
- 生存分析比较了NBN变种的携带者与野生类型 (WT) 状态.
主要成果:
- 在4183名B-ALL患者中,在50名患者中确定了25种可能有害的NBN变异,与对照组相比,显示出明显的过度代表性 (OR=1.77,p=0.004).
- 在25个变体中,14个被验证为致病性或可能致病性,原因是严重的功能丧失表型.
- 异合体生殖系NBN变异携带者表现出与WT个体相似的生存结果.
结论:
- 生殖线NBN变异与儿科B-ALL倾向有显著的相关性.
- 发现的致病性NBN变体具有严重的功能丧失效应.
- 异卵性NBN变种携带者可以安全地接受B-ALL治疗,这表明对生存没有不利影响.
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