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Evaluation of Candidate Stromal Epithelial Cross-Talk Genes Identifies Association between Risk of Serous Ovarian Cancer and TERT, a Cancer Susceptibility "Hot-Spot''

Johnatty, SE; Beesley, J; Chen, XQ; Macgregor, S; Duffy, DL; Spurdle, AB; deFazio, A; ... Ovarian Canc Assoc Consortium; + view all (2010) Evaluation of Candidate Stromal Epithelial Cross-Talk Genes Identifies Association between Risk of Serous Ovarian Cancer and TERT, a Cancer Susceptibility "Hot-Spot''. PLOS GENET , 6 (7) , Article e1001016. 10.1371/journal.pgen.1001016. Green open access

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Abstract

We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n = 675) and controls (n = 1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n = 1,233 serous invasive cases; n = 3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. Pper-allele >= 0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele=0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p = 0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.

Type: Article
Title: Evaluation of Candidate Stromal Epithelial Cross-Talk Genes Identifies Association between Risk of Serous Ovarian Cancer and TERT, a Cancer Susceptibility "Hot-Spot''
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pgen.1001016
Publisher version: http://dx.doi.org/10.1371/journal.pgen.1001016
Language: English
Additional information: © 2010 Johnatty et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: ACS/AOCS - National Health and Medical Research Council of Australia (#199600, ACS study; GC-T and PMW); U.S. Army Medical Research and Materiel Command under DAMD17-01-1-0729, Award no. W81XWH-06-1-0220; the Cancer Council Tasmania and Cancer Foundation of Western Australia; Westmead Millennium Foundation and the Westmead Gynaecological Oncology Research Fund, Westmead Hospital, Westmead, NSW, Australia (NG). DOVE - NIH R01CA112523 and RO1 CA87538. HOPE - National Cancer Institute, Award number R01CA095023. The GER (German Ovarian Cancer Study or GOCS) was supported by the German Federal Ministry of Education and Research of Germany, Programme of Clinical Biomedical Research grant 01 GB 9401, the genotyping in part by the state of Baden-Württemberg through Medical Faculty of the University of Ulm (P.685) and data management by the German Cancer Research Center. UCI - National Cancer Institute grants CA-58860, CA-92044 and the Lon V. Smith Foundation grant LVS-39420. NECC - National Cancer Institute R01CA54419 and P50CA105009. MAY - National Institutes of Health R01-CA122443. PBCS (POL) - Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. HAWAII - US Public Health Service grant R01-CA-58598, and contracts N01-CN-55424 and N01-PC-67001 from the National Cancer Institute, NIH, Department of Health and Human Services. SEARCH - programme grant from Cancer Research UK. UKOPS - The work of SAG, SJR, AG-M, and UM was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. The UKOPS study was funded by the Oak Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: GENOME-WIDE ASSOCIATION, SINGLE-NUCLEOTIDE POLYMORPHISMS, INCESSANT OVULATION, COLORECTAL-CANCER, EXPRESSION, CONSORTIUM, VARIANTS, PROSTATE, LOCUS, MYC
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/191664
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