Abstract
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.
Highlights
Cancer is frequently characterized by genetic alterations accompanied by epigenetic changes
We found that rs2853677 is located within the Snail1 binding site in a telomerase reverse transcriptase (TERT) enhancer
We have previously shown that the intronic enhancer physically interacts with the TERT promoter by looping out the intervening sequences
Summary
Cancer is frequently characterized by genetic alterations accompanied by epigenetic changes. Another two SNPs (rs2853677 at 5p15.33 and rs2741354 at 8q21.1) have been reported to be associated with lung cancer in Japanese and European populations, respectively [10, 11] How these SNPs affect lung cancer susceptibility is completely unknown. We investigated these 6 previously reported risk loci and confirmed that rs2853677 in the second intron of the telomerase reverse transcriptase (TERT) gene is associated with a high risk of lung adenocarcinoma in the Han Chinese population. Our data implicate that rs2853677 may be a potential biomarker for prognosis in Snail associated cancer
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