前列腺癌风险 SNP rs10993994 是通过 MSMB 介导的 SNHG11 的跨表达数量性状基因座。
Prostate cancer risk SNP rs10993994 is a trans-eQTL for SNHG11 mediated through MSMB.
机构信息
Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genome Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Program in Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
出版信息
Hum Mol Genet. 2020 Jun 27;29(10):1581-1591. doi: 10.1093/hmg/ddaa026.
How genome-wide association studies-identified single-nucleotide polymorphisms (SNPs) affect remote genes remains unknown. Expression quantitative trait locus (eQTL) association meta-analysis on 496 prostate tumor and 602 normal prostate samples with 117 SNPs revealed novel cis-eQTLs and trans-eQTLs. Mediation testing and colocalization analysis demonstrate that MSMB is a cis-acting mediator for SNHG11 (P < 0.01). Removing rs10993994 in LNCaP cell lines by CRISPR/Cas9 editing shows that the C-allele corresponds with an over 100-fold increase in MSMB expression and 5-fold increase in SNHG11 compared with the T-allele. Colocalization analysis confirmed that the same set of SNPs associated with MSMB expression is associated with SNHG11 expression (posterior probability of shared variants is 66.6% in tumor and 91.4% in benign). These analyses further demonstrate variants driving MSMB expression differ in tumor and normal, suggesting regulatory network rewiring during tumorigenesis.
全基因组关联研究鉴定的单核苷酸多态性（SNPs）如何影响远程基因尚不清楚。对 496 个前列腺肿瘤和 602 个正常前列腺样本的 117 个 SNP 进行表达数量性状基因座（eQTL）关联荟萃分析，揭示了新的顺式-eQTL 和反式-eQTL。中介测试和共定位分析表明，MSMB 是 SNHG11 的顺式作用介体（P < 0.01）。通过 CRISPR/Cas9 编辑去除 LNCaP 细胞系中的 rs10993994，结果表明 C 等位基因与 MSMB 表达增加 100 多倍，与 T 等位基因相比 SNHG11 表达增加 5 倍。共定位分析证实，与 MSMB 表达相关的同一组 SNP 与 SNHG11 表达相关（肿瘤中共享变异的后验概率为 66.6%，良性组织中为 91.4%）。这些分析进一步表明，驱动 MSMB 表达的变体在肿瘤和正常组织中存在差异，这表明在肿瘤发生过程中调控网络的重排。
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