Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci
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Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci. / Kar, Siddhartha P; Adler, Emily; Tyrer, Jonathan; Hazelett, Dennis J; Anton-Culver, Hoda; Bandera, Elisa V; Beckmann, Matthias W; Berchuck, Andrew; Bogdanova, Natalia; Brinton, Louise; Butzow, Ralf; Campbell, Ian; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Dansonka-Mieszkowska, Agnieszka; Doherty, Jennifer Anne; Dörk, Thilo; Dürst, Matthias; Eccles, Diana; Fasching, Peter A; Flanagan, James M; Gentry-Maharaj, Aleksandra; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T; Gronwald, Jacek; Heitz, Florian; T Hildebrandt, Michelle A; Høgdall, Estrid; Høgdall, Claus K; Huntsman, David G; Jensen, Allan; Karlan, Beth Y; Kelemen, Linda E; Kiemeney, Lambertus A; Kjaer, Susanne Krüger; Kupryjanczyk, Jolanta; Lambrechts, Diether; Levine, Douglas A; Li, Qiyuan; Lissowska, Jolanta; Lu, Karen H; Lubiński, Jan; Massuger, Leon F A G; McGuire, Valerie; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Monteiro, Alvaro N A; Moysich, Kirsten B; Ness, Roberta B; Nevanlinna, Heli; Paul, James; Pearce, Celeste L; Pejovic, Tanja; Permuth, Jennifer B; Phelan, Catherine; Pike, Malcolm C; Poole, Elizabeth M; Ramus, Susan J; Risch, Harvey A; Rossing, Mary Anne; Salvesen, Helga B; Schildkraut, Joellen M; Sellers, Thomas A; Sherman, Mark E; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa; Terry, Kathryn L; Tworoger, Shelley S; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S; Wu, Anna H; Yang, Hannah P; Zheng, Wei; Ziogas, Argyrios; Freedman, Matthew L; Gayther, Simon A; Pharoah, Paul P D; Lawrenson, Kate.
in: BRIT J CANCER, Jahrgang 116, Nr. 4, 14.02.2017, S. 524-535.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci
AU - Kar, Siddhartha P
AU - Adler, Emily
AU - Tyrer, Jonathan
AU - Hazelett, Dennis J
AU - Anton-Culver, Hoda
AU - Bandera, Elisa V
AU - Beckmann, Matthias W
AU - Berchuck, Andrew
AU - Bogdanova, Natalia
AU - Brinton, Louise
AU - Butzow, Ralf
AU - Campbell, Ian
AU - Carty, Karen
AU - Chang-Claude, Jenny
AU - Cook, Linda S
AU - Cramer, Daniel W
AU - Cunningham, Julie M
AU - Dansonka-Mieszkowska, Agnieszka
AU - Doherty, Jennifer Anne
AU - Dörk, Thilo
AU - Dürst, Matthias
AU - Eccles, Diana
AU - Fasching, Peter A
AU - Flanagan, James M
AU - Gentry-Maharaj, Aleksandra
AU - Glasspool, Rosalind
AU - Goode, Ellen L
AU - Goodman, Marc T
AU - Gronwald, Jacek
AU - Heitz, Florian
AU - T Hildebrandt, Michelle A
AU - Høgdall, Estrid
AU - Høgdall, Claus K
AU - Huntsman, David G
AU - Jensen, Allan
AU - Karlan, Beth Y
AU - Kelemen, Linda E
AU - Kiemeney, Lambertus A
AU - Kjaer, Susanne Krüger
AU - Kupryjanczyk, Jolanta
AU - Lambrechts, Diether
AU - Levine, Douglas A
AU - Li, Qiyuan
AU - Lissowska, Jolanta
AU - Lu, Karen H
AU - Lubiński, Jan
AU - Massuger, Leon F A G
AU - McGuire, Valerie
AU - McNeish, Iain
AU - Menon, Usha
AU - Modugno, Francesmary
AU - Monteiro, Alvaro N A
AU - Moysich, Kirsten B
AU - Ness, Roberta B
AU - Nevanlinna, Heli
AU - Paul, James
AU - Pearce, Celeste L
AU - Pejovic, Tanja
AU - Permuth, Jennifer B
AU - Phelan, Catherine
AU - Pike, Malcolm C
AU - Poole, Elizabeth M
AU - Ramus, Susan J
AU - Risch, Harvey A
AU - Rossing, Mary Anne
AU - Salvesen, Helga B
AU - Schildkraut, Joellen M
AU - Sellers, Thomas A
AU - Sherman, Mark E
AU - Siddiqui, Nadeem
AU - Sieh, Weiva
AU - Song, Honglin
AU - Southey, Melissa
AU - Terry, Kathryn L
AU - Tworoger, Shelley S
AU - Walsh, Christine
AU - Wentzensen, Nicolas
AU - Whittemore, Alice S
AU - Wu, Anna H
AU - Yang, Hannah P
AU - Zheng, Wei
AU - Ziogas, Argyrios
AU - Freedman, Matthew L
AU - Gayther, Simon A
AU - Pharoah, Paul P D
AU - Lawrenson, Kate
PY - 2017/2/14
Y1 - 2017/2/14
N2 - 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.
AB - 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.
KW - Case-Control Studies
KW - Cell Line, Tumor
KW - Cell Transformation, Neoplastic
KW - Cystadenocarcinoma, Serous
KW - Female
KW - Gene Amplification
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Neoplastic
KW - Genetic Loci
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Humans
KW - Meta-Analysis as Topic
KW - Microarray Analysis
KW - Neoplasms, Glandular and Epithelial
KW - Ovarian Neoplasms
KW - Polymorphism, Single Nucleotide
KW - Journal Article
U2 - 10.1038/bjc.2016.426
DO - 10.1038/bjc.2016.426
M3 - SCORING: Journal article
C2 - 28103614
VL - 116
SP - 524
EP - 535
JO - BRIT J CANCER
JF - BRIT J CANCER
SN - 0007-0920
IS - 4
ER -