Oncotarget

Research Papers:

Functional dissection of breast cancer risk-associated TERT promoter variants

Sonja Helbig _, Leesa Wockner, Annick Bouendeu, Ursula Hille-Betz, Karen McCue, Juliet D. French, Stacey L. Edwards, Hilda A. Pickett, Roger R. Reddel, Georgia Chenevix-Trench, Thilo Dörk and Jonathan Beesley

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:67203-67217. https://doi.org/10.18632/oncotarget.18226

Metrics: HTML 1613 views  |   ?  


Abstract

Sonja Helbig1,2, Leesa Wockner3, Annick Bouendeu1, Ursula Hille-Betz1, Karen McCue2, Juliet D. French2, Stacey L. Edwards2, Hilda A. Pickett4, Roger R. Reddel5, Georgia Chenevix-Trench2, Thilo Dörk1,* and Jonathan Beesley2,*

1Gynaecology Research Unit, Hannover Medical School, Hannover, Germany

2Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia

3Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia

4Telomere Length Regulation Unit, Children’s Medical Research Institute, University of Sydney, Westmead, Australia

5Cancer Research Unit, Children’s Medical Research Institute, University of Sydney, Westmead, Australia

*Shared senior authors

Correspondence to:

Sonja Helbig, email: Helbig.Sonja@mh-hannover.de

Keywords: telomerase, SNP, breast carcinoma, GABPA, GWAS

Received: November 04, 2016    Accepted: May 02, 2017    Published: May 26, 2017

ABSTRACT

The multi-cancer susceptibility locus at 5p15.33 includes TERT, encoding the telomerase catalytic subunit. Genome-wide association studies (GWAS) have identified six single nucleotide polymorphisms (SNPs) in the TERT promoter associated with decreased breast cancer risk, although the precise causal variants and their mechanisms of action have remained elusive. Luciferase reporter assays indicated that the protective haplotype reduced TERT promoter activity in human mammary epithelial and cancer cells in an estrogen-independent manner. Using single variant constructs, we identified rs3215401 and rs2853669 as likely functional variants. Silencing of MYC decreased TERT promoter activity but neither MYC nor ETS2 silencing conferred allele-specificity. In chromatin immunoprecipitation experiments, the ETS protein GABPA, but not ETS2 or ELF1, bound rs2853669 in an allele-specific manner in mammary epithelial cells. Investigation of open chromatin in mammoplasty samples suggested involvement of three additional variants, though not rs3215401 or rs2853669. Chromosome conformation capture revealed no interaction of the TERT promoter with regulatory elements in the locus, indicating limited local impact of candidate variants on the TERT promoter. Collectively, our functional studies of the TERT-CLPTM1L breast cancer susceptibility locus describe rs2853669 as a functional variant of this association signal among three other potentially causal variants and demonstrate the versatile mechanisms by which TERT promoter variants may affect breast cancer risk.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 18226