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. 2023 Jul;149(8):4515-4522.
doi: 10.1007/s00432-022-04372-9. Epub 2022 Sep 21.

Identification of rs2736099 as a novel cis-regulatory variation for TERT and implications for tumorigenesis and cell proliferation

Qiang Shi  1 , Xin-Xin Zhang  2 , Xiao-Qian Shi  2 , Ying Chen  2 , Chang Sun  3
Affiliations

Identification of rs2736099 as a novel cis-regulatory variation for TERT and implications for tumorigenesis and cell proliferation

Qiang Shi et al. J Cancer Res Clin Oncol. 2023 Jul.

Abstract

Purpose: Lung cancer is a malignant tumor with obvious genetic predisposition. Association studies have proposed that rs2853677, a SNP localizing at intron region of TERT (telomerase reverse transcriptase), is significantly associated with TERT expression, telomere length and eventually lung cancer risk. However, functional genomics work indicates that rs2853677 is not with the ability to alter gene expression. All these facts make us hypothesize that some other genetic variation(s) are in linkage disequilibrium (LD) with rs2853677 and influence TERT expression.

Methods: LD pattern in rs2853677 nearby region was analyzed based on 1000 genomes data for three representative populations in the world and functional genomics research was performed for this locus.

Results: Only one SNP, rs2736099, is in strong LD with rs2853677 in East Asian. Dual-luciferase reporter assay verifies that rs2736099 can regulate gene expression and should be the causal SNP for this disease. Through chromosome conformation capture assay, it is disclosed that the enhancer surrounding rs2736099 can interact with TERT promoter. Through chromatin immunoprecipitation, the transcription factor SP1 (Sp1 transcription factor) is recognized for the chromatin segment spanning rs2736099.

Conclusions: Our results provide the missing piece between genetic variation at this locus and lung cancer risk, which is also applied to tumorigenesis in other tissues and cell proliferation.

Keywords: Expression regulation; Lung cancer; TERT; rs2736099; rs2853677.

PubMed Disclaimer

Conflict of interest statement

The authors have no relevant financial or non-financial interests to disclose.

Figures

Fig. 1
Fig. 1
Luciferase expression of plasmid constructs containing rs2853677 and rs2736099 alleles in A549 cell. Each bar represents one plasmid. The x axis is proportional to the relative luciferase amount. All data is normalized by original construct and displayed as mean ± standard deviation (SD). * P < 0.0001
Fig. 2
Fig. 2
Interaction efficiency between the enhancer containing rs2736099 and other genome regions in 5p15.33. The x axis designates the position of restrictive fragments in chr5 while the y axis shows the relative interaction efficiency. The schematic location and transcript direction of different genes within this region are represented by the arrows at top. All data is displayed as mean ± SD
Fig. 3
Fig. 3
ChIP result in A549 cell for the rs2736099 surrounding region. The y axis denotes relative enrichment relative to input. All data is displayed as mean ± SD. * P < 10–5
Fig. 4
Fig. 4
Difference in the binding affinity between rs2736099 alleles and A549 nuclear proteins. NE represents nuclear extract, and the arrow points out the location of protein-probe complex
See this image and copyright information in PMC

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