Search for rare protein altering variants influencing susceptibility to multiple myeloma.
Search for rare protein altering variants influencing susceptibility to multiple myeloma.
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DOI：
10.18632/oncotarget.15874
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发表时间：
2017-05-30
期刊：
影响因子：
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通讯作者：
Morgan GJ
中科院分区：
文献类型：
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作者：
Scales M;Chubb D;Dobbins SE;Johnson DC;Li N;Sternberg MJ;Weinhold N;Stein C;Jackson G;Davies FE;Walker BA;Wardell CP;Houlston RS;Morgan GJ
发生多发性骨髓瘤（MM）的遗传风险的遗传基础在很大程度上是未知的。为了研究罕见蛋白改变变异对MM发病风险的影响，我们分析了513例MM病例和1569名健康对照者的高覆盖率外显子组测序数据，并进行了单变异和基因负担测试。我们没有发现任何与MM相关的中等影响的重复编码低频等位基因（1-5%）。然而，在基因负担分析中，我们确实发现了骨髓着丝点微管间质基因KIF18A的变异与MM风险之间有希望的关系，KIF18A在控制有丝分裂染色体定位动力学中起作用（P =3.6×10−6）。进一步的分析表明，KIF18A在MM的分子亚组中表现出独特的表达模式，并与患者生存率相关。我们的结果为未来的研究设计提供了信息，并为确定候选MM易感基因的影响提供了资源。
The genetic basis underlying the inherited risk of developing multiple myeloma (MM) is largely unknown. To examine the impact of rare protein altering variants on the risk of developing MM we analyzed high-coverage exome sequencing data on 513 MM cases and 1,569 healthy controls, performing both single variant and gene burden tests. We did not identify any recurrent coding low-frequency alleles (1–5%) with moderate effect that were statistically associated with MM. In a gene burden analysis we did however identify a promising relationship between variation in the marrow kinetochore microtubule stromal gene KIF18A, which plays a role in control mitotic chromosome positioning dynamics, and risk of MM (P =3.6×10−6). Further analysis showed KIF18A displays a distinct pattern of expression across molecular subgroups of MM as well as being associated with patient survival. Our results inform future study design and provide a resource for contextualizing the impact of candidate MM susceptibility genes.