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

Siddhartha P. Kar, Emily Adler, Jonathan Tyrer, Dennis Hazelett, Hoda Anton-Culver, Elisa V. Bandera, Matthias W. Beckmann, Andrew Berchuck, Natalia Bogdanova, Louise Brinton, Ralf Butzow, Ian Campbell, Karen Carty, Jenny Chang-Claude, Linda S. Cook, Daniel W. Cramer, Julie M Cunningham, Agnieszka Dansonka-Mieszkowska, Jennifer Anne Doherty, Thilo DörkMatthias Dürst, Diana Eccles, Peter A. Fasching, James Flanagan, Aleksandra Gentry-Maharaj, Rosalind Glasspool, Ellen L Goode, Marc T. Goodman, Jacek Gronwald, Florian Heitz, Michelle A T Hildebrandt, Estrid Høgdall, Claus K. Høgdall, David G. Huntsman, Allan Jensen, Beth Y. Karlan, Linda E. Kelemen, Lambertus A. Kiemeney, Susanne K. Kjaer, Jolanta Kupryjanczyk, Diether Lambrechts, Douglas A. Levine, Qiyuan Li, Jolanta Lissowska, Karen H. Lu, Jan Lubiński, Leon F A G Massuger, Valerie McGuire, Iain McNeish, Usha Menon, Francesmary Modugno, Alvaro N. Monteiro, Kirsten B. Moysich, Roberta B. Ness, Heli Nevanlinna, James Paul, Celeste L. Pearce, Tanja Pejovic, Jennifer B. Permuth, Catherine Phelan, Malcolm C. Pike, Elizabeth M. Poole, Susan J. Ramus, Harvey A. Risch, Mary Anne Rossing, Helga B. Salvesen, Joellen M. Schildkraut, Thomas A. Sellers, Mark E. Sherman, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa Southey, Kathryn L. Terry, Shelley S. Tworoger, Christine Walsh, Nicolas Wentzensen, Alice S. Whittemore, Anna H. Wu, Hannah Yang, Wei Zheng, Argyrios Ziogas, Matthew L. Freedman, Simon A. Gayther, Paul D P Pharoah, Kate Lawrenson

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 (P GSEA <0.001; FDR=0.21), 7/615 in the replication (P GSEA =0.004; FDR=0.37), and 1/615 in the combined (P GSEA <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 (P GSEA =0.025) and IGROV1 (P GSEA =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.

Original languageEnglish (US)
Pages (from-to)524-535
Number of pages12
JournalBritish Journal of Cancer
Volume116
Issue number4
DOIs
StatePublished - Feb 14 2017

Fingerprint

Ovarian Neoplasms
Genes
Genome-Wide Association Study
Ovarian epithelial cancer
Transcription Factors
Chemical Databases
Genetic Association Studies
Small Interfering RNA
Carcinogenesis
Gene Expression
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kar, S. P., Adler, E., Tyrer, J., Hazelett, D., Anton-Culver, H., Bandera, E. V., ... Lawrenson, K. (2017). Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci. British Journal of Cancer, 116(4), 524-535. https://doi.org/10.1038/bjc.2016.426

Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci. / Kar, Siddhartha P.; Adler, Emily; Tyrer, Jonathan; Hazelett, Dennis; 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; Gentry-Maharaj, Aleksandra; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T.; Gronwald, Jacek; Heitz, Florian; Hildebrandt, Michelle A T; Høgdall, Estrid; Høgdall, Claus K.; Huntsman, David G.; Jensen, Allan; Karlan, Beth Y.; Kelemen, Linda E.; Kiemeney, Lambertus A.; Kjaer, Susanne K.; 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.; 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; Zheng, Wei; Ziogas, Argyrios; Freedman, Matthew L.; Gayther, Simon A.; Pharoah, Paul D P; Lawrenson, Kate.

In: British Journal of Cancer, Vol. 116, No. 4, 14.02.2017, p. 524-535.

Research output: Contribution to journalArticle

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, Dörk, T, Dürst, M, Eccles, D, Fasching, PA, Flanagan, J, Gentry-Maharaj, A, Glasspool, R, Goode, EL, Goodman, MT, Gronwald, J, Heitz, F, Hildebrandt, MAT, Høgdall, E, Høgdall, 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, Lubiński, 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, ME, 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 2017, 'Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci', British Journal of Cancer, vol. 116, no. 4, pp. 524-535. https://doi.org/10.1038/bjc.2016.426
Kar, Siddhartha P. ; Adler, Emily ; Tyrer, Jonathan ; Hazelett, Dennis ; 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 ; Gentry-Maharaj, Aleksandra ; Glasspool, Rosalind ; Goode, Ellen L ; Goodman, Marc T. ; Gronwald, Jacek ; Heitz, Florian ; Hildebrandt, Michelle A T ; Høgdall, Estrid ; Høgdall, Claus K. ; Huntsman, David G. ; Jensen, Allan ; Karlan, Beth Y. ; Kelemen, Linda E. ; Kiemeney, Lambertus A. ; Kjaer, Susanne K. ; 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. ; 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 ; Zheng, Wei ; Ziogas, Argyrios ; Freedman, Matthew L. ; Gayther, Simon A. ; Pharoah, Paul D P ; Lawrenson, Kate. / Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci. In: British Journal of Cancer. 2017 ; Vol. 116, No. 4. pp. 524-535.
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title = "Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci",
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 (P GSEA <0.001; FDR=0.21), 7/615 in the replication (P GSEA =0.004; FDR=0.37), and 1/615 in the combined (P GSEA <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 (P GSEA =0.025) and IGROV1 (P GSEA =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.",
author = "Kar, {Siddhartha P.} and Emily Adler and Jonathan Tyrer and Dennis Hazelett and Hoda Anton-Culver and Bandera, {Elisa V.} and Beckmann, {Matthias W.} and Andrew Berchuck and Natalia Bogdanova and Louise Brinton and Ralf Butzow and Ian Campbell and Karen Carty and Jenny Chang-Claude and Cook, {Linda S.} and Cramer, {Daniel W.} and Cunningham, {Julie M} and Agnieszka Dansonka-Mieszkowska and Doherty, {Jennifer Anne} and Thilo D{\"o}rk and Matthias D{\"u}rst and Diana Eccles and Fasching, {Peter A.} and James Flanagan and Aleksandra Gentry-Maharaj and Rosalind Glasspool and Goode, {Ellen L} and Goodman, {Marc T.} and Jacek Gronwald and Florian Heitz and Hildebrandt, {Michelle A T} and Estrid H{\o}gdall and H{\o}gdall, {Claus K.} and Huntsman, {David G.} and Allan Jensen and Karlan, {Beth Y.} and Kelemen, {Linda E.} and Kiemeney, {Lambertus A.} and Kjaer, {Susanne K.} and Jolanta Kupryjanczyk and Diether Lambrechts and Levine, {Douglas A.} and Qiyuan Li and Jolanta Lissowska and Lu, {Karen H.} and Jan Lubiński and Massuger, {Leon F A G} and Valerie McGuire and Iain McNeish and Usha Menon and Francesmary Modugno and Monteiro, {Alvaro N.} and Moysich, {Kirsten B.} and Ness, {Roberta B.} and Heli Nevanlinna and James Paul and Pearce, {Celeste L.} and Tanja Pejovic and Permuth, {Jennifer B.} and Catherine Phelan and Pike, {Malcolm C.} and Poole, {Elizabeth M.} and Ramus, {Susan J.} and Risch, {Harvey A.} and Rossing, {Mary Anne} and Salvesen, {Helga B.} and Schildkraut, {Joellen M.} and Sellers, {Thomas A.} and Sherman, {Mark E.} and Nadeem Siddiqui and Weiva Sieh and Honglin Song and Melissa Southey and Terry, {Kathryn L.} and Tworoger, {Shelley S.} and Christine Walsh and Nicolas Wentzensen and Whittemore, {Alice S.} and Wu, {Anna H.} and Hannah Yang and Wei Zheng and Argyrios Ziogas and Freedman, {Matthew L.} and Gayther, {Simon A.} and Pharoah, {Paul D P} and Kate Lawrenson",
year = "2017",
month = "2",
day = "14",
doi = "10.1038/bjc.2016.426",
language = "English (US)",
volume = "116",
pages = "524--535",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
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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

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

AU - Gentry-Maharaj, Aleksandra

AU - Glasspool, Rosalind

AU - Goode, Ellen L

AU - Goodman, Marc T.

AU - Gronwald, Jacek

AU - Heitz, Florian

AU - Hildebrandt, Michelle A T

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 K.

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.

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

AU - Zheng, Wei

AU - Ziogas, Argyrios

AU - Freedman, Matthew L.

AU - Gayther, Simon A.

AU - Pharoah, Paul D P

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 (P GSEA <0.001; FDR=0.21), 7/615 in the replication (P GSEA =0.004; FDR=0.37), and 1/615 in the combined (P GSEA <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 (P GSEA =0.025) and IGROV1 (P GSEA =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 (P GSEA <0.001; FDR=0.21), 7/615 in the replication (P GSEA =0.004; FDR=0.37), and 1/615 in the combined (P GSEA <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 (P GSEA =0.025) and IGROV1 (P GSEA =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.

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U2 - 10.1038/bjc.2016.426

DO - 10.1038/bjc.2016.426

M3 - Article

C2 - 28103614

AN - SCOPUS:85010004839

VL - 116

SP - 524

EP - 535

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 4

ER -