Rs2853677 modulates Snail1 binding to the TERT enhancer and affects lung adenocarcinoma susceptibility.

Rs2853677 modulates Snail1 binding to the TERT enhancer and affects lung adenocarcinoma susceptibility.

Genome wide association studies (GWAS) have shown that SNPs in non-coding regions are associated with inherited susceptibility to cancer. The effect of one single SNP, however, is weak. To identify potential co-factors of SNPs, we investigated the underlying mechanism by which SNPs affect lung cancer susceptibility. We found that rs2853677 is located within the Snail1 binding site in a TERT enhancer. This enhancer increases TERT transcription when juxtaposed to the TERT promoter. The binding of Snail1 to the enhancer disrupts enhancer-promoter colocalization and silences TERT transcription. The high risk variant of rs2853677 disrupts the Snail1 binding site and derepresses TERT expression in response to Snail1 upregulation, thus increasing lung adenocarcinoma susceptibility. Our data suggest that Snail1 may be a co-factor of rs2853677 for predicting lung adenocarcinoma susceptibility and prognosis.

全基因组关联研究（GWAS）表明，非编码区域的单核苷酸多态性（SNP）与癌症的遗传易感性相关。然而，单个SNP的作用很微弱。为了确定SNP的潜在辅助因子，我们研究了SNP影响肺癌易感性的潜在机制。我们发现rs2853677位于端粒酶逆转录酶（TERT）增强子中的Snail1结合位点内。当这个增强子与TERT启动子并列时，它会增加TERT的转录。Snail1与增强子的结合会破坏增强子 - 启动子的共定位，并使TERT转录沉默。rs2853677的高风险变异会破坏Snail1结合位点，并在Snail1上调时解除对TERT表达的抑制，从而增加肺腺癌的易感性。我们的数据表明，Snail1可能是rs2853677用于预测肺腺癌易感性和预后的一个辅助因子。