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非洲祖先获得功能的HOXB13变体的临床和功能分析涉及侵袭性前列腺癌
Mayuko Kanayama1, Yidong Chen2, Daniel Rabizadeh1
1Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
HOXB13 (X285K) 前列腺癌变体在黑人男性中更常见,并与侵略性疾病有关. 这种变异通过改变基因表达来驱动癌症,类似于BRCA2突变.
科学领域:
- 遗传学 遗传学 是一个
- 在瘤学瘤学.
- 分子生物学分子生物学
背景情况:
- 一种HOXB13变种 (X285K) 与西非血统男性的前列腺癌有关.
- 霍克斯B13 (X285K) 变种的临床意义和功能机制在很大程度上是未知的.
研究的目的:
- 评估HOXB13 (X285K) 与HOXB13 (G84E) 和BRCA2致病/可能致病 (P/LP) 变体相比的临床相关性.
- 研究由HOXB13 (X285K) 蛋白驱动的致癌机制.
主要方法:
- 对21,393名前列腺癌患者 (2019-2022) 的真实世界遗传测试数据的分析.
- 使用细胞系模型进行体外功能研究,包括RNA测序,ChIP测序和西欧斑块.
- 种族/种族群体之间的变异频率的比较以及与疾病侵略性的相关性 (格里森得分,AJCC阶段).
主要成果:
- 在自我报告的黑人患者中,HOXB13 (X285K) 的发生率明显高 (1.01%) 比白人患者 (0.01%).
- 与HOXB13 (G84E) 携带者相比,在HOXB13 (X285K) 和BRCA2 P/LP携带者中观察到更具侵略性的前列腺癌趋势.
- X285K 蛋白质表现出功能的增加,通过增强促进剂/增强剂结合来对E2F/MYC目标基因 (cyclin B1,c-Myc) 进行上调,而不会影响雄激素反应.
结论:
- HOXB13 (X285K) 是一种与侵袭性前列腺癌相关的临床相关变体,特别是在黑人男性中.
- 这种X285K变异赋予了与BRCA2突变相似的攻击性特征,由一个独特的功能获取机制驱动,涉及E2F/MYC通路失调.
- 建议黑人男性进行HOXB13 (X285K) 基因检测,建议早期查变种携带者.
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