文章：

共定位遗传关联揭示10个基因座中可变剪接变异体作为乳腺癌风险的候选因果联系

Colocalised Genetic Associations Reveal Alternative Splicing Variants as Candidate Causal Links for Breast Cancer Risk in 10 Loci

原文发布日期：29 August 2024

DOI: 10.3390/cancers16173020

类型: Article

开放获取: 是

英文摘要：

Genome-wide association studies (GWASs) have revealed numerous loci associated with breast cancer risk, yet the precise causal variants, their impact on molecular mechanisms, and the affected genes often remain elusive. We hypothesised that specific variants exert their influence by affecting cis-regulatory alternative splice elements. An analysis of splicing quantitative trait loci (sQTL) in healthy breast tissue from female individuals identified multiple variants linked to alterations in splicing ratios. Through colocalisation analysis, we pinpointed 43 variants within twelve genes that serve as candidate causal links between sQTL and GWAS findings. In silico splice analysis highlighted a potential mechanism for three genes—FDPS,SGCE, andMRPL11—where variants in proximity to or on the splice site modulate usage, resulting in alternative splice transcripts. Further in vitro/vivo studies are imperative to fully understand how these identified changes contribute to breast oncogenesis. Moreover, investigating their potential as biomarkers for breast cancer risk could enhance screening strategies and early detection methods for breast cancer.

摘要翻译： 

全基因组关联研究（GWAS）已揭示众多与乳腺癌风险相关的基因位点，然而确切的致病变异、其对分子机制的影响以及相关靶基因往往仍不明确。我们假设特定变异通过影响顺式调控选择性剪接元件发挥作用。通过对女性健康乳腺组织的剪接数量性状位点（sQTL）分析，我们发现了多个与剪接比例改变相关的变异。通过共定位分析，我们在12个基因中确定了43个变异，这些变异可作为连接sQTL与GWAS发现的潜在因果关联。计算剪接分析揭示了FDPS、SGCE和MRPL11三个基因的可能作用机制——位于剪接位点附近或之上的变异通过调控位点使用率，产生不同的选择性剪接转录本。要全面理解这些已识别的变化如何促进乳腺癌发生，必须开展进一步的体外/体内研究。此外，探索其作为乳腺癌风险生物标志物的潜力，有望优化乳腺癌筛查策略与早期检测方法。

原文链接：

Colocalised Genetic Associations Reveal Alternative Splicing Variants as Candidate Causal Links for Breast Cancer Risk in 10 Loci