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 | |
| State | Published - Oct 1 2015 |
ASJC Scopus subject areas
- Epidemiology
- Oncology
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Network-based integration of GWAS and gene expression identifies a HOX-centric network associated with serous ovarian cancer risk. / Kar, Siddhartha P.; Tyrer, Jonathan P.; Li, Qiyuan; Lawrenson, Kate; Aben, Katja K.H.; Anton-Culver, Hoda; Antonenkova, Natalia; Chenevix-Trench, Georgia; Baker, Helen; Bandera, Elisa V.; Bean, Yukie T.; Beckmann, Matthias W.; Berchuck, Andrew; Bisogna, Maria; Bjørge, Line; Bogdanova, Natalia; Brinton, Louise; Brooks-Wilson, Angela; Butzow, Ralf; Campbell, Ian; Carty, Karen; Chang-Claude, Jenny; Chen, Yian Ann; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; Du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas F.; Edwards, Robert P.; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goode, Ellen L.; Goodman, Marc T.; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus K.; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Paul, James; Jensen, Allan; Ji, Bu Tian; Karlan, Beth Y.; Kjaer, Susanne K.; Kelemen, Linda E.; Kellar, Melissa; Kelley, Joseph; Kiemeney, Lambertus A.; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Iain A.; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B.; Narod, Steven A.; Nedergaard, Lotte; Ness, Roberta B.; Nevanlinna, Heli; Kunleodunsi; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Pearce, Celeste Leigh; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Phelan, Catherine M.; Pike, Malcolm C.; Poole, Elizabeth M.; Ramus, Susan J.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schildkraut, Joellen M.; Schwaab, Ira; Shu, Xiao Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Sucheston-Campbell, Lara E.; Tangen, Ingvild L.; Teo, Soo Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Timorek, Agnieszka; Tsai, Ya Yu; Tworoger, Shelley S.; Van Altena, Anne M.; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A.; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Woo, Yin Ling; Wu, Xifeng; Wu, Anna; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Sellers, Thomas A.; Monteiro, Alvaro N.A.; Freedman, Matthew L.; Gayther, Simon A.; Pharoah, Paul D.P.
In: Cancer Epidemiology Biomarkers and Prevention, Vol. 24, No. 10, 01.10.2015, p. 1574-1584.Research output: Contribution to journal › Article › peer-review
}
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.
N1 - Publisher Copyright: © 2015 American Association for Cancer Research. Copyright: Copyright 2015 Elsevier B.V., All rights reserved.
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 -