Volume 10 Supplement 2

Familial Aspects of Cancer 2011 Research and Practice

Open Access

Functional polymorphisms in the TERT promoter are associated with risk of serious ovarian and breast cancer

  • Jonathan Beesley1, 8,
  • Hilda Pickett2, 3,
  • Sharon Johnatty1,
  • Xiaoqing Chen1,
  • Jun Jun Li1,
  • David Rider4,
  • Michael Stutz2, 3,
  • Diether Lambrecht5, 6,
  • Jenny Chang-Claude7,
  • Thilo Dork9,
  • Marc Goodman10,
  • Bart Kiemmney11, 12, 13,
  • Elisa Bandera14,
  • Linda Kelemen15,
  • Shan Wang-Gorke6,
  • Ian Campbell16,
  • Simon Gayther17,
  • Susan Ramus17,
  • Ellen Goode4,
  • Roger Reddel2, 3,
  • Georgia Chenevix-Trench1,
  • kConFab Investigators and
  • Australian Ovarian Cancer Study Group
Hereditary Cancer in Clinical Practice201210(Suppl 2):A86


Published: 12 April 2012

Genome-wide association studies have implicated the TERT-CLPTM1L locus at 5p15.33 in susceptibility to a variety of cancers including pancreas, lung, skin and glioma, suggesting that TERT may act as a “pan-cancer susceptibility locus” in a similar manner to the 8q24 region.

We initially identified an association between an intronic TERT SNP rs7726159 and epithelial ovarian cancer (EOC) risk through an Illumina GoldenGate scan of single nucleotide polymorphisms (SNPs) in candidate genes, with a more pronounced effect in serous cases (Johnatty et al, PloS Genetics 2010). We employed a fine-mapping strategy of a 500 kb region of the TERT-CLPTM1L locus using data from the 1000Genomes and HapMap Projects, and cases and controls from the Ovarian Cancer Association Consortium (OCAC). Using single-marker and stepwise logistic regression adjusted for age and study, we analysed 28 SNPs in 2,130 invasive epithelial ovarian cancer cases, including 1,076 of serous histology, and 3,975 controls of Caucasian ancestry from nine OCAC studies, and observed a significant association between serous cases and a TERT promoter SNP rs2736109 [adj. ORper-allele 0.86 (0.77-0.96), P = 0.005].

Since much of the genetic architecture is shared between EOC and breast cancer, we analysed rs2736109 in 4,277 invasive breast cancer cases and 7,000 controls from the Breast Cancer Association Consortium (BCAC). Although there was no association with invasive breast cancer risk overall [adj. ORper-allele = 0.95 (0.90 - 1.01) P = 0.10], we found the strongest evidence of association among ER-negative cases over the age of 50 (n=636) [adj. ORper-allele 0.84 (0.75-0.95), P = 0.005].

To examine the potential functional consequences of rs2736109 and another promoter SNP, rs2736108, we generated luciferase reporter constructs comprising 3.7 kb of the TERT promoter containing various combinations of alleles and transfected them into breast and ovarian cell lines. We observed a decrease in luciferase expression by the presence of both the A alleles at rs2736108 and rs2736109, but not when either allele is present alone. Our analysis of 345 Australian controls suggests that the A-A haplotype at rs2736108 and rs2736109 occurs with a frequency of 32%, suggesting that this relatively common promoter haplotype may lower the risk of serous epithelial ovarian cancer though decreasing TERT expression.

Authors’ Affiliations

Division of Genetics and Population Health, Queensland Institute of Medical Research
Cancer Research Unit, Children's Medical Research Institute
Sydney Medical School, University of Sydney
Department of Health Sciences Research, Mayo Clinic College of Medicine
Vesalius Research Center, VIB
Vesalius Research Center, University of Leuven
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ)
Department of Obstetrics and Gynecology, University of Ulm
Clinics of Obstetrics and Gynaecology, Hannover Medical School
Cancer Epidemiology Program, University of Hawaii Cancer Center
Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre
Department of Urology, Radboud University Nijmegen Medical Centre
Comprehensive Cancer Center, The Netherlands
The Cancer Institute of New Jersey, Robert Wood Johnson Medical School
Department of Population Health Research, Alberta Health Services-Cancer Care
Peter MacCallum Cancer Centre
Department of Preventive Medicine, Keck School of Medicine, University of Southern California


© Beesley et al; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.