Network-based integration of GWAS and gene expression identifies a HOX-centric network associated with serous ovarian cancer risk

Siddhartha P. Kar; Jonathan P. Tyrer; Qiyuan Li; Kate Lawrenson; Katja K.H. Aben; Hoda Anton-Culver; Natalia Antonenkova; Georgia Chenevix-Trench; Helen Baker; Elisa V. Bandera; Yukie T. Bean; Matthias W. Beckmann; Andrew Berchuck; Maria Bisogna; Line Bjørge; Natalia Bogdanova; Louise Brinton; Angela Brooks-Wilson; Ralf Butzow; Ian Campbell; Karen Carty; Jenny Chang-Claude; Yian Ann Chen; Zhihua Chen; Linda S. Cook; Daniel Cramer; Julie M. Cunningham; Cezary Cybulski; Agnieszka Dansonka-Mieszkowska; Joe Dennis; Ed Dicks; Jennifer A. Doherty; Thilo Dörk; Andreas Du Bois; Matthias Dürst; Diana Eccles; Douglas F. Easton; Robert P. Edwards; Arif B. Ekici; Peter A. Fasching; Brooke L. Fridley; Yu Tang Gao; Aleksandra Gentry-Maharaj; Graham G. Giles; Rosalind Glasspool; Ellen L. Goode; Marc T. Goodman; Jacek Grownwald; Patricia Harrington; Philipp Harter; Alexander Hein; Florian Heitz; Michelle A.T. Hildebrandt; Peter Hillemanns; Estrid Hogdall; Claus K. Hogdall; Satoyo Hosono; Edwin S. Iversen; Anna Jakubowska; James Paul; Allan Jensen; Bu Tian Ji; Beth Y. Karlan; Susanne K. Kjaer; Linda E. Kelemen; Melissa Kellar; Joseph Kelley; Lambertus A. Kiemeney; Camilla Krakstad; Jolanta Kupryjanczyk; Diether Lambrechts; Sandrina Lambrechts; Nhu D. Le; Alice W. Lee; Shashi Lele; Arto Leminen; Jenny Lester; Douglas A. Levine; Dong Liang; Jolanta Lissowska; Karen Lu; Jan Lubinski; Lene Lundvall; Leon Massuger; Keitaro Matsuo; Valerie McGuire; John R. McLaughlin; Iain A. McNeish; Usha Menon; Francesmary Modugno; Kirsten B. Moysich; Steven A. Narod; Lotte Nedergaard; Roberta B. Ness; Heli Nevanlinna; Kunleodunsi; Sara H. Olson; Irene Orlow; Sandra Orsulic; Rachel Palmieri Weber; Celeste Leigh Pearce; Tanja Pejovic; Liisa M. Pelttari; Jennifer Permuth-Wey; Catherine M. Phelan; Malcolm C. Pike; Elizabeth M. Poole; Susan J. Ramus; Harvey A. Risch; Barry Rosen; Mary Anne Rossing; Joseph H. Rothstein; Anja Rudolph; Ingo B. Runnebaum; Iwona K. Rzepecka; Helga B. Salvesen; Joellen M. Schildkraut; Ira Schwaab; Xiao Ou Shu; Yurii B. Shvetsov; Nadeem Siddiqui; Weiva Sieh; Honglin Song; Melissa C. Southey; Lara E. Sucheston-Campbell; Ingvild L. Tangen; Soo Hwang Teo; Kathryn L. Terry; Pamela J. Thompson; Agnieszka Timorek; Ya Yu Tsai; Shelley S. Tworoger; Anne M. Van Altena; Els Van Nieuwenhuysen; Ignace Vergote; Robert A. Vierkant; Shan Wang-Gohrke; Christine Walsh; Nicolas Wentzensen; Alice S. Whittemore; Kristine G. Wicklund; Lynne R. Wilkens; Yin Ling Woo; Xifeng Wu; Anna Wu; Hannah Yang; Wei Zheng; Argyrios Ziogas; Thomas A. Sellers; Alvaro N.A. Monteiro; Matthew L. Freedman; Simon A. Gayther; Paul D.P. Pharoah

doi:10.1158/1055-9965.EPI-14-1270

Network-based integration of GWAS and gene expression identifies a HOX-centric network associated with serous ovarian cancer risk

Siddhartha P. Kar, Jonathan P. Tyrer, Qiyuan Li, Kate Lawrenson, Katja K.H. Aben, Hoda Anton-Culver, Natalia Antonenkova, Georgia Chenevix-Trench, Helen Baker, Elisa V. Bandera, Yukie T. Bean, Matthias W. Beckmann, Andrew Berchuck, Maria Bisogna, Line Bjørge, Natalia Bogdanova, Louise Brinton, Angela Brooks-Wilson, Ralf Butzow, Ian CampbellKaren Carty, Jenny Chang-Claude, Yian Ann Chen, Zhihua Chen, Linda S. Cook, Daniel Cramer, Julie M. Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Joe Dennis, Ed Dicks, Jennifer A. Doherty, Thilo Dörk, Andreas Du Bois, Matthias Dürst, Diana Eccles, Douglas F. Easton, Robert P. Edwards, Arif B. Ekici, Peter A. Fasching, Brooke L. Fridley, Yu Tang Gao, Aleksandra Gentry-Maharaj, Graham G. Giles, Rosalind Glasspool, Ellen L. Goode, Marc T. Goodman, Jacek Grownwald, Patricia Harrington, Philipp Harter, Alexander Hein, Florian Heitz, Michelle A.T. Hildebrandt, Peter Hillemanns, Estrid Hogdall, Claus K. Hogdall, Satoyo Hosono, Edwin S. Iversen, Anna Jakubowska, James Paul, Allan Jensen, Bu Tian Ji, Beth Y. Karlan, Susanne K. Kjaer, Linda E. Kelemen, Melissa Kellar, Joseph Kelley, Lambertus A. Kiemeney, Camilla Krakstad, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D. Le, Alice W. Lee, Shashi Lele, Arto Leminen, Jenny Lester, Douglas A. Levine, Dong Liang, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon Massuger, Keitaro Matsuo, Valerie McGuire, John R. McLaughlin, Iain A. McNeish, Usha Menon, Francesmary Modugno, Kirsten B. Moysich, Steven A. Narod, Lotte Nedergaard, Roberta B. Ness, Heli Nevanlinna, Kunleodunsi, Sara H. Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, Celeste Leigh Pearce, Tanja Pejovic, Liisa M. Pelttari, Jennifer Permuth-Wey, Catherine M. Phelan, Malcolm C. Pike, Elizabeth M. Poole, Susan J. Ramus, Harvey A. Risch, Barry Rosen, Mary Anne Rossing, Joseph H. Rothstein, Anja Rudolph, Ingo B. Runnebaum, Iwona K. Rzepecka, Helga B. Salvesen, Joellen M. Schildkraut, Ira Schwaab, Xiao Ou Shu, Yurii B. Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C. Southey, Lara E. Sucheston-Campbell, Ingvild L. Tangen, Soo Hwang Teo, Kathryn L. Terry, Pamela J. Thompson, Agnieszka Timorek, Ya Yu Tsai, Shelley S. Tworoger, Anne M. Van Altena, Els Van Nieuwenhuysen, Ignace Vergote, Robert A. Vierkant, Shan Wang-Gohrke, Christine Walsh, Nicolas Wentzensen, Alice S. Whittemore, Kristine G. Wicklund, Lynne R. Wilkens, Yin Ling Woo, Xifeng Wu, Anna Wu, Hannah Yang, Wei Zheng, Argyrios Ziogas, Thomas A. Sellers, Alvaro N.A. Monteiro, Matthew L. Freedman, Simon A. Gayther, Paul D.P. Pharoah

Obstetrics & Gynecology

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.

Original language	English (US)
Pages (from-to)	1574-1584
Number of pages	11
Journal	Cancer Epidemiology Biomarkers and Prevention
Volume	24
Issue number	10
DOIs	https://doi.org/10.1158/1055-9965.EPI-14-1270
State	Published - Oct 1 2015

ASJC Scopus subject areas

Epidemiology
Oncology

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10.1158/1055-9965.EPI-14-1270

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Kar, S. P., Tyrer, J. P., Li, Q., Lawrenson, K., Aben, K. K. H., Anton-Culver, H., Antonenkova, N., Chenevix-Trench, G., Baker, H., Bandera, E. V., Bean, Y. T., Beckmann, M. W., Berchuck, A., Bisogna, M., Bjørge, L., Bogdanova, N., Brinton, L., Brooks-Wilson, A., Butzow, R., ... Pharoah, P. D. P. (2015). Network-based integration of GWAS and gene expression identifies a HOX-centric network associated with serous ovarian cancer risk. Cancer Epidemiology Biomarkers and Prevention, 24(10), 1574-1584. https://doi.org/10.1158/1055-9965.EPI-14-1270

Kar, SP, Tyrer, JP, Li, Q, Lawrenson, K, Aben, KKH, Anton-Culver, H, Antonenkova, N, Chenevix-Trench, G, Baker, H, Bandera, EV, Bean, YT, Beckmann, MW, Berchuck, A, Bisogna, M, Bjørge, L, Bogdanova, N, Brinton, L, Brooks-Wilson, A, Butzow, R, Campbell, I, Carty, K, Chang-Claude, J, Chen, YA, Chen, Z, Cook, LS, Cramer, D, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, Du Bois, A, Dürst, M, Eccles, D, Easton, DF, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Grownwald, J, Harrington, P, Harter, P, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, CK, Hosono, S, Iversen, ES, Jakubowska, A, Paul, J, Jensen, A, Ji, BT, Karlan, BY, Kjaer, SK, Kelemen, LE, Kellar, M, Kelley, J, Kiemeney, LA, Krakstad, C, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, L, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, IA, Menon, U, Modugno, F, Moysich, KB, Narod, SA, Nedergaard, L, Ness, RB, Nevanlinna, H, Kunleodunsi, Olson, SH, Orlow, I, Orsulic, S, Weber, RP, Pearce, CL, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Phelan, CM, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schildkraut, JM, Schwaab, I, Shu, XO, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Sucheston-Campbell, LE, Tangen, IL, Teo, SH, Terry, KL, Thompson, PJ, Timorek, A, Tsai, YY, Tworoger, SS, Van Altena, AM, Van Nieuwenhuysen, E, Vergote, I, Vierkant, RA, Wang-Gohrke, S, Walsh, C, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Woo, YL, Wu, X, Wu, A, Yang, H, Zheng, W, Ziogas, A, Sellers, TA, Monteiro, ANA, Freedman, ML, Gayther, SA & Pharoah, PDP 2015, 'Network-based integration of GWAS and gene expression identifies a HOX-centric network associated with serous ovarian cancer risk', Cancer Epidemiology Biomarkers and Prevention, vol. 24, no. 10, pp. 1574-1584. https://doi.org/10.1158/1055-9965.EPI-14-1270

@article{d3b1b0833a8b4b359ac1d0fcc663b980,

title = "Network-based integration of GWAS and gene expression identifies a HOX-centric network associated with serous ovarian cancer risk",

abstract = "Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.",

author = "Kar, {Siddhartha P.} and Tyrer, {Jonathan P.} and Qiyuan Li and Kate Lawrenson and Aben, {Katja K.H.} and Hoda Anton-Culver and Natalia Antonenkova and Georgia Chenevix-Trench and Helen Baker and Bandera, {Elisa V.} and Bean, {Yukie T.} and Beckmann, {Matthias W.} and Andrew Berchuck and Maria Bisogna and Line Bj{\o}rge and Natalia Bogdanova and Louise Brinton and Angela Brooks-Wilson and Ralf Butzow and Ian Campbell and Karen Carty and Jenny Chang-Claude and Chen, {Yian Ann} and Zhihua Chen and Cook, {Linda S.} and Daniel Cramer and Cunningham, {Julie M.} and Cezary Cybulski and Agnieszka Dansonka-Mieszkowska and Joe Dennis and Ed Dicks and Doherty, {Jennifer A.} and Thilo D{\"o}rk and {Du Bois}, Andreas and Matthias D{\"u}rst and Diana Eccles and Easton, {Douglas F.} and Edwards, {Robert P.} and Ekici, {Arif B.} and Fasching, {Peter A.} and Fridley, {Brooke L.} and Gao, {Yu Tang} and Aleksandra Gentry-Maharaj and Giles, {Graham G.} and Rosalind Glasspool and Goode, {Ellen L.} and Goodman, {Marc T.} and Jacek Grownwald and Patricia Harrington and Philipp Harter and Alexander Hein and Florian Heitz and Hildebrandt, {Michelle A.T.} and Peter Hillemanns and Estrid Hogdall and Hogdall, {Claus K.} and Satoyo Hosono and Iversen, {Edwin S.} and Anna Jakubowska and James Paul and Allan Jensen and Ji, {Bu Tian} and Karlan, {Beth Y.} and Kjaer, {Susanne K.} and Kelemen, {Linda E.} and Melissa Kellar and Joseph Kelley and Kiemeney, {Lambertus A.} and Camilla Krakstad and Jolanta Kupryjanczyk and Diether Lambrechts and Sandrina Lambrechts and Le, {Nhu D.} and Lee, {Alice W.} and Shashi Lele and Arto Leminen and Jenny Lester and Levine, {Douglas A.} and Dong Liang and Jolanta Lissowska and Karen Lu and Jan Lubinski and Lene Lundvall and Leon Massuger and Keitaro Matsuo and Valerie McGuire and McLaughlin, {John R.} and McNeish, {Iain A.} and Usha Menon and Francesmary Modugno and Moysich, {Kirsten B.} and Narod, {Steven A.} and Lotte Nedergaard and Ness, {Roberta B.} and Heli Nevanlinna and Kunleodunsi and Olson, {Sara H.} and Irene Orlow and Sandra Orsulic and Weber, {Rachel Palmieri} and Pearce, {Celeste Leigh} and Tanja Pejovic and Pelttari, {Liisa M.} and Jennifer Permuth-Wey and Phelan, {Catherine M.} and Pike, {Malcolm C.} and Poole, {Elizabeth M.} and Ramus, {Susan J.} and Risch, {Harvey A.} and Barry Rosen and Rossing, {Mary Anne} and Rothstein, {Joseph H.} and Anja Rudolph and Runnebaum, {Ingo B.} and Rzepecka, {Iwona K.} and Salvesen, {Helga B.} and Schildkraut, {Joellen M.} and Ira Schwaab and Shu, {Xiao Ou} and Shvetsov, {Yurii B.} and Nadeem Siddiqui and Weiva Sieh and Honglin Song and Southey, {Melissa C.} and Sucheston-Campbell, {Lara E.} and Tangen, {Ingvild L.} and Teo, {Soo Hwang} and Terry, {Kathryn L.} and Thompson, {Pamela J.} and Agnieszka Timorek and Tsai, {Ya Yu} and Tworoger, {Shelley S.} and {Van Altena}, {Anne M.} and {Van Nieuwenhuysen}, Els and Ignace Vergote and Vierkant, {Robert A.} and Shan Wang-Gohrke and Christine Walsh and Nicolas Wentzensen and Whittemore, {Alice S.} and Wicklund, {Kristine G.} and Wilkens, {Lynne R.} and Woo, {Yin Ling} and Xifeng Wu and Anna Wu and Hannah Yang and Wei Zheng and Argyrios Ziogas and Sellers, {Thomas A.} and Monteiro, {Alvaro N.A.} and Freedman, {Matthew L.} and Gayther, {Simon A.} and Pharoah, {Paul D.P.}",

note = "Publisher Copyright: {\textcopyright} 2015 American Association for Cancer Research.",

year = "2015",

month = oct,

day = "1",

doi = "10.1158/1055-9965.EPI-14-1270",

language = "English (US)",

volume = "24",

pages = "1574--1584",

journal = "Cancer Epidemiology Biomarkers and Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research Inc.",

number = "10",

}

TY - JOUR

T1 - Network-based integration of GWAS and gene expression identifies a HOX-centric network associated with serous ovarian cancer risk

AU - Kar, Siddhartha P.

AU - Tyrer, Jonathan P.

AU - Li, Qiyuan

AU - Lawrenson, Kate

AU - Aben, Katja K.H.

AU - Anton-Culver, Hoda

AU - Antonenkova, Natalia

AU - Chenevix-Trench, Georgia

AU - Baker, Helen

AU - Bandera, Elisa V.

AU - Bean, Yukie T.

AU - Beckmann, Matthias W.

AU - Berchuck, Andrew

AU - Bisogna, Maria

AU - Bjørge, Line

AU - Bogdanova, Natalia

AU - Brinton, Louise

AU - Brooks-Wilson, Angela

AU - Butzow, Ralf

AU - Campbell, Ian

AU - Carty, Karen

AU - Chang-Claude, Jenny

AU - Chen, Yian Ann

AU - Chen, Zhihua

AU - Cook, Linda S.

AU - Cramer, Daniel

AU - Cunningham, Julie M.

AU - Cybulski, Cezary

AU - Dansonka-Mieszkowska, Agnieszka

AU - Dennis, Joe

AU - Dicks, Ed

AU - Doherty, Jennifer A.

AU - Dörk, Thilo

AU - Du Bois, Andreas

AU - Dürst, Matthias

AU - Eccles, Diana

AU - Easton, Douglas F.

AU - Edwards, Robert P.

AU - Ekici, Arif B.

AU - Fasching, Peter A.

AU - Fridley, Brooke L.

AU - Gao, Yu Tang

AU - Gentry-Maharaj, Aleksandra

AU - Giles, Graham G.

AU - Glasspool, Rosalind

AU - Goode, Ellen L.

AU - Goodman, Marc T.

AU - Grownwald, Jacek

AU - Harrington, Patricia

AU - Harter, Philipp

AU - Hein, Alexander

AU - Heitz, Florian

AU - Hildebrandt, Michelle A.T.

AU - Hillemanns, Peter

AU - Hogdall, Estrid

AU - Hogdall, Claus K.

AU - Hosono, Satoyo

AU - Iversen, Edwin S.

AU - Jakubowska, Anna

AU - Paul, James

AU - Jensen, Allan

AU - Ji, Bu Tian

AU - Karlan, Beth Y.

AU - Kjaer, Susanne K.

AU - Kelemen, Linda E.

AU - Kellar, Melissa

AU - Kelley, Joseph

AU - Kiemeney, Lambertus A.

AU - Krakstad, Camilla

AU - Kupryjanczyk, Jolanta

AU - Lambrechts, Diether

AU - Lambrechts, Sandrina

AU - Le, Nhu D.

AU - Lee, Alice W.

AU - Lele, Shashi

AU - Leminen, Arto

AU - Lester, Jenny

AU - Levine, Douglas A.

AU - Liang, Dong

AU - Lissowska, Jolanta

AU - Lu, Karen

AU - Lubinski, Jan

AU - Lundvall, Lene

AU - Massuger, Leon

AU - Matsuo, Keitaro

AU - McGuire, Valerie

AU - McLaughlin, John R.

AU - McNeish, Iain A.

AU - Menon, Usha

AU - Modugno, Francesmary

AU - Moysich, Kirsten B.

AU - Narod, Steven A.

AU - Nedergaard, Lotte

AU - Ness, Roberta B.

AU - Nevanlinna, Heli

AU - Kunleodunsi,

AU - Olson, Sara H.

AU - Orlow, Irene

AU - Orsulic, Sandra

AU - Weber, Rachel Palmieri

AU - Pearce, Celeste Leigh

AU - Pejovic, Tanja

AU - Pelttari, Liisa M.

AU - Permuth-Wey, Jennifer

AU - Phelan, Catherine M.

AU - Pike, Malcolm C.

AU - Poole, Elizabeth M.

AU - Ramus, Susan J.

AU - Risch, Harvey A.

AU - Rosen, Barry

AU - Rossing, Mary Anne

AU - Rothstein, Joseph H.

AU - Rudolph, Anja

AU - Runnebaum, Ingo B.

AU - Rzepecka, Iwona K.

AU - Salvesen, Helga B.

AU - Schildkraut, Joellen M.

AU - Schwaab, Ira

AU - Shu, Xiao Ou

AU - Shvetsov, Yurii B.

AU - Siddiqui, Nadeem

AU - Sieh, Weiva

AU - Song, Honglin

AU - Southey, Melissa C.

AU - Sucheston-Campbell, Lara E.

AU - Tangen, Ingvild L.

AU - Teo, Soo Hwang

AU - Terry, Kathryn L.

AU - Thompson, Pamela J.

AU - Timorek, Agnieszka

AU - Tsai, Ya Yu

AU - Tworoger, Shelley S.

AU - Van Altena, Anne M.

AU - Van Nieuwenhuysen, Els

AU - Vergote, Ignace

AU - Vierkant, Robert A.

AU - Wang-Gohrke, Shan

AU - Walsh, Christine

AU - Wentzensen, Nicolas

AU - Whittemore, Alice S.

AU - Wicklund, Kristine G.

AU - Wilkens, Lynne R.

AU - Woo, Yin Ling

AU - Wu, Xifeng

AU - Wu, Anna

AU - Yang, Hannah

AU - Zheng, Wei

AU - Ziogas, Argyrios

AU - Sellers, Thomas A.

AU - Monteiro, Alvaro N.A.

AU - Freedman, Matthew L.

AU - Gayther, Simon A.

AU - Pharoah, Paul D.P.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.

AB - Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.

UR - http://www.scopus.com/inward/record.url?scp=84942870326&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84942870326&partnerID=8YFLogxK

U2 - 10.1158/1055-9965.EPI-14-1270

DO - 10.1158/1055-9965.EPI-14-1270

M3 - Article

C2 - 26209509

AN - SCOPUS:84942870326

VL - 24

SP - 1574

EP - 1584

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

SN - 1055-9965

IS - 10

ER -

Network-based integration of GWAS and gene expression identifies a HOX-centric network associated with serous ovarian cancer risk

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