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 |
|---|---|
| Pages (from-to) | 1574-1584 |
| Number of pages | 11 |
| Journal | Cancer Epidemiology, Biomarkers & Prevention |
| Volume | 24 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - Oct 2015 |
| Externally published | Yes |
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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 Tarumi; 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 Anne; Dörk, Thilo; Du Bois, Andreas; Dürst, Matthias; Eccles, Diana M; 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 M; 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 Krüger; 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 M.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; McNeish, Iain A; Menon, Usha N; 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 Birgitte; 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; Altena, Anne Mvan; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A; Wang-Gohrke, Shan; Walsh, Christine S; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R.; Woo, Yin Ling; Wu, Xifeng; Wu, Anna H; Yang, Hannah P; Zheng, Wei; Ziogas, Argyrios; Sellers, Thomas A; Monteiro, Alvaro N.A.; Freedman, Matthew L; Gayther, Simon A; Pharoah, Paul D P; on behalf of the Australian Cancer Study; on behalf of the Australian Ovarian Cancer Study Group.
In: Cancer Epidemiology, Biomarkers & Prevention, Vol. 24, No. 10, 10.2015, p. 1574-1584.Research output: Contribution to journal › Article › Research › 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 Tarumi
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 Anne
AU - Dörk, Thilo
AU - Du Bois, Andreas
AU - Dürst, Matthias
AU - Eccles, Diana M
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 M
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 Krüger
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 M.
AU - Matsuo, Keitaro
AU - McGuire, Valerie
AU - McLaughlin, John R
AU - McNeish, Iain A
AU - Menon, Usha N
AU - Modugno, Francesmary
AU - Moysich, Kirsten B
AU - Narod, Steven A
AU - Nedergaard, Lotte
AU - Ness, Roberta B
AU - Nevanlinna, Heli
AU - Kunleodunsi, null
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 Birgitte
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 - Altena, Anne Mvan
AU - Van Nieuwenhuysen, Els
AU - Vergote, Ignace
AU - Vierkant, Robert A
AU - Wang-Gohrke, Shan
AU - Walsh, Christine S
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 H
AU - Yang, Hannah P
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
AU - on behalf of the Australian Cancer Study
AU - on behalf of the Australian Ovarian Cancer Study Group
PY - 2015/10
Y1 - 2015/10
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
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 & Prevention
JF - Cancer Epidemiology, Biomarkers & Prevention
SN - 1055-9965
IS - 10
ER -