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对癌的多祖先全基因组关联研究确定了63个易感区域

Mark P Purdue¹, Diptavo Dutta², Mitchell J Machiela²

¹Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. purduem@mail.nih.gov.

Nature genetics

|April 26, 2024

概括

这项大规模的全基因组研究确定了108个癌遗传风险位,包括新的区域和非洲祖先个体中显著的VHL基因变异. 这些发现有助于更好地了解癌遗传学和风险预测.

科学领域:

遗传学是一个遗传学.
在瘤学瘤学.
基因组学就是基因组学.

背景情况:

癌,特别是清细胞细胞癌 (RCC),具有复杂的遗传基础,尚未完全理解.
全基因组关联研究 (GWAS) 对于识别遗传敏感性位置至关重要.
以前的研究已经确定了一些遗传因素,但需要对各种祖先进行全面的了解.

研究的目的:

进行一个大规模的,多祖先的全基因组关联研究的元分析,以确定对癌的遗传易感性区域.
通过癌亚型 (清细胞RCC和乳头RCC) 分层调查遗传关联.
探索已识别的变异的功能影响及其与基因表达和生物通路的关系.

主要方法:

一个多祖先全基因组关联研究元分析,涉及29,020例癌病例和835,670例对照.
对透明细胞RCC和乳头类RCC亚型进行了分层分析.
使用cis-eQTL分析将遗传变异与候选基因联系起来.

主要成果:

确定了63个易感区域,其中50个是新鲜的,有108个独立的癌风险位.
相关52个区域 (78个位点) 具有清晰细胞RCC和6个区域 (7个位点) 具有乳头RCC.
发现了非洲祖先个体中常见的VHL基因变异 (rs7629500),显著增加了清细胞RCC风险 (OR 2.72).
通过cis-eQTL分析确定了83个候选基因,并发现缺氧诱导因子结合部位的丰富,这表明缺氧在癌发病过程中的作用.
在欧洲祖先的个体中开发了多基因风险得分,AUC为0.65 (0.74与风险因素).

结论:

这项研究显著扩大了与多个祖先的癌易感性相关的已知遗传基因位置的景观.
这些发现强调了低氧相关机制在癌发展中的重要性.
鉴定出的基因架构为功能研究提供了基础,并改善了对癌的多基因风险预测.

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