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Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci

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Title: Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci
Authors: Kar, SP
Adler, E
Tyrer, J
Hazelett, D
Anton-Culver, H
Bandera, EV
Beckmann, MW
Berchuck, A
Bogdanova, N
Brinton, L
Butzow, R
Campbell, I
Carty, K
Chang-Claude, J
Cook, LS
Cramer, DW
Cunningham, JM
Dansonka-Mieszkowska, A
Doherty, JA
Doerk, T
Duerst, M
Eccles, D
Fasching, PA
Flanagan, J
Gentry-Maharaj, A
Glasspool, R
Goode, EL
Goodman, MT
Gronwald, J
Heitz, F
Hildebrandt, MAT
Hogdall, E
Hogdall, CK
Huntsman, DG
Jensen, A
Karlan, BY
Kelemen, LE
Kiemeney, LA
Kjaer, SK
Kupryjanczyk, J
Lambrechts, D
Levine, DA
Li, Q
Lissowska, J
Lu, KH
Lubinski, J
Massuger, LFAG
McGuire, V
McNeish, I
Menon, U
Modugno, F
Monteiro, AN
Moysich, KB
Ness, RB
Nevanlinna, H
Paul, J
Pearce, CL
Pejovic, T
Permuth, JB
Phelan, C
Pike, MC
Poole, EM
Ramus, SJ
Risch, HA
Rossing, MA
Salvesen, HB
Schildkraut, JM
Sellers, TA
Sherman, M
Siddiqui, N
Sieh, W
Song, H
Southey, M
Terry, KL
Tworoger, SS
Walsh, C
Wentzensen, N
Whittemore, AS
Wu, AH
Yang, H
Zheng, W
Ziogas, A
Freedman, ML
Gayther, SA
Pharoah, PDP
Lawrenson, K
Item Type: Journal Article
Abstract: Background: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. Methods: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). Results: The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10−5 (including six with P<5 × 10−8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. Conclusions: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.
Issue Date: 19-Jan-2017
Date of Acceptance: 29-Nov-2016
URI: http://hdl.handle.net/10044/1/45621
DOI: https://dx.doi.org/10.1038/bjc.2016.426
ISSN: 0007-0920
Publisher: NATURE PUBLISHING GROUP
Start Page: 524
End Page: 535
Journal / Book Title: BRITISH JOURNAL OF CANCER
Volume: 116
Issue: 4
Copyright Statement: © 2017 Cancer Research UK. All rights reserved.
Sponsor/Funder: Cancer Research UK
Funder's Grant Number: C536/A13086
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
serous ovarian cancer
transcription factor
PAX8
genome-wide association study
gene set enrichment analysis
GENOME-WIDE ASSOCIATION
FUNCTIONAL-CHARACTERIZATION
RISK LOCI
EXPRESSION
GWAS
IDENTIFICATION
PROSTATE
BREAST
CELLS
VARIANTS
Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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