Imperial College London
Portrait Picture

DR JAMES M. FLANAGAN

Faculty of Medicine, Department of Surgery & Cancer

Reader in Epigenetics
 
 
 
//

Contact

 

+44 (0)20 7594 2127j.flanagan

 
 
//

Location

 

Institute of Reproductive and Developmental BiologyHammersmith Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Kar:2017:10.1038/bjc.2016.426,
author = {Kar, SP and Adler, E and Tyrer, J and Hazelett, D and Anton-Culver, H and Bandera, EV and Beckmann, MW and Berchuck, A and Bogdanova, N and Brinton, L and Butzow, R and Campbell, I and Carty, K and Chang-Claude, J and Cook, LS and Cramer, DW and Cunningham, JM and Dansonka-Mieszkowska, A and Doherty, JA and Doerk, T and Duerst, M and Eccles, D and Fasching, PA and Flanagan, J and Gentry-Maharaj, A and Glasspool, R and Goode, EL and Goodman, MT and Gronwald, J and Heitz, F and Hildebrandt, MAT and Hogdall, E and Hogdall, CK and Huntsman, DG and Jensen, A and Karlan, BY and Kelemen, LE and Kiemeney, LA and Kjaer, SK and Kupryjanczyk, J and Lambrechts, D and Levine, DA and Li, Q and Lissowska, J and Lu, KH and Lubinski, J and Massuger, LFAG and McGuire, V and McNeish, I and Menon, U and Modugno, F and Monteiro, AN and Moysich, KB and Ness, RB and Nevanlinna, H and Paul, J and Pearce, CL and Pejovic, T and Permuth, JB and Phelan, C and Pike, MC and Poole, EM and Ramus, SJ and Risch, HA and},
doi = {10.1038/bjc.2016.426},
journal = {BRITISH JOURNAL OF CANCER},
pages = {524--535},
title = {Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci},
url = {http://dx.doi.org/10.1038/bjc.2016.426},
volume = {116},
year = {2017}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
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.
AU  - Kar,SP
AU  - Adler,E
AU  - Tyrer,J
AU  - Hazelett,D
AU  - Anton-Culver,H
AU  - Bandera,EV
AU  - Beckmann,MW
AU  - Berchuck,A
AU  - Bogdanova,N
AU  - Brinton,L
AU  - Butzow,R
AU  - Campbell,I
AU  - Carty,K
AU  - Chang-Claude,J
AU  - Cook,LS
AU  - Cramer,DW
AU  - Cunningham,JM
AU  - Dansonka-Mieszkowska,A
AU  - Doherty,JA
AU  - Doerk,T
AU  - Duerst,M
AU  - Eccles,D
AU  - Fasching,PA
AU  - Flanagan,J
AU  - Gentry-Maharaj,A
AU  - Glasspool,R
AU  - Goode,EL
AU  - Goodman,MT
AU  - Gronwald,J
AU  - Heitz,F
AU  - Hildebrandt,MAT
AU  - Hogdall,E
AU  - Hogdall,CK
AU  - Huntsman,DG
AU  - Jensen,A
AU  - Karlan,BY
AU  - Kelemen,LE
AU  - Kiemeney,LA
AU  - Kjaer,SK
AU  - Kupryjanczyk,J
AU  - Lambrechts,D
AU  - Levine,DA
AU  - Li,Q
AU  - Lissowska,J
AU  - Lu,KH
AU  - Lubinski,J
AU  - Massuger,LFAG
AU  - McGuire,V
AU  - McNeish,I
AU  - Menon,U
AU  - Modugno,F
AU  - Monteiro,AN
AU  - Moysich,KB
AU  - Ness,RB
AU  - Nevanlinna,H
AU  - Paul,J
AU  - Pearce,CL
AU  - Pejovic,T
AU  - Permuth,JB
AU  - Phelan,C
AU  - Pike,MC
AU  - Poole,EM
AU  - Ramus,SJ
AU  - Risch,HA
AU  - Rossing,MA
AU  - Salvesen,HB
AU  - Schildkraut,JM
AU  - Sellers,TA
AU  - Sherman,M
AU  - Siddiqui,N
AU  - Sieh,W
AU  - Song,H
AU  - Southey,M
AU  - Terry,KL
AU  - Tworoger,SS
AU  - Walsh,C
AU  - Wentzensen,N
AU  - Whittemore,AS
AU  - Wu,AH
AU  - Yang,H
AU  - Zheng,W
AU  - Ziogas,A
AU  - Freedman,ML
AU  - Gayther,SA
AU  - Pharoah,PDP
AU  - Lawrenson,K
DO  - 10.1038/bjc.2016.426
EP  - 535
PY  - 2017///
SN  - 0007-0920
SP  - 524
TI  - Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci
T2  - BRITISH JOURNAL OF CANCER
UR  - http://dx.doi.org/10.1038/bjc.2016.426
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000394446600014&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/45621
VL  - 116
ER  -
Download