title: Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot".
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>or=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.
authors.affiliation: Queensland Institute of Medical Research, Brisbane, Australia. sharonJo@qimr.edu.au
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Johnatty
authors.forename: Jonathan
authors.initials: J
authors.lastname: Beesley
authors.forename: Xiaoqing
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authors.lastname: Chen
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authors.forename: David L
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authors.forename: Penelope M
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authors.lastname: Rossing
authors.forename: Jennifer Anne
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authors.lastname: Doherty
authors.forename: Marc T
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authors.lastname: Goodman
authors.forename: Galina
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authors.lastname: Lurie
authors.forename: Pamela J
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authors.lastname: Thompson
authors.forename: Lynne R
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authors.forename: Roberta B
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authors.forename: Kirsten B
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authors.lastname: Moysich
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authors.lastname: Wang-Gohrke
authors.forename: Daniel W
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authors.forename: Kathryn L
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authors.lastname: Terry
authors.forename: Susan E
authors.initials: SE
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authors.forename: Shelley S
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authors.forename: Montserrat
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authors.lastname: Garcia-Closas
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authors.forename: Jolanta
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authors.lastname: Song
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authors.lastname: Whitemore
authors.forename: Celeste L
authors.initials: CL
authors.lastname: Pearce
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
authors.forename: Anna H
authors.initials: AH
authors.lastname: Wu
authors.forename: Malcolm C
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authors.lastname: Pike
authors.forename: Simon A
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authors.lastname: Gayther
authors.forename: Susan J
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authors.lastname: Ramus
authors.forename: Usha
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authors.lastname: Menon
authors.forename: Aleksandra
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authors.lastname: Gentry-Maharaj
authors.forename: Hoda
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authors.lastname: Anton-Culver
authors.forename: Argyrios
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authors.lastname: Ziogas
authors.forename: Estrid
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authors.lastname: Hogdall
authors.forename: Susanne K
authors.initials: SK
authors.lastname: Kjaer
authors.forename: Claus
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authors.lastname: Hogdall
authors.forename: Andrew
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authors.lastname: Berchuck
authors.forename: Joellen M
authors.initials: JM
authors.lastname: Schildkraut
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Iversen
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Moorman
authors.forename: Catherine M
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authors.lastname: Phelan
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Sellers
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vierkant
authors.forename: David N
authors.initials: DN
authors.lastname: Rider
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.forename: Izhak
authors.initials: I
authors.lastname: Haviv
authors.forename: Georgia
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authors.lastname: Chenevix-Trench
mesh_terms: D016022:Case-Control Studies; D002895:Chromosomes, Human, Pair 5; D004847:Epithelial Cells / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017154:Stromal Cells / Q000473:pathology*; D019098:Telomerase / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D019098:Telomerase