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; Estrid Hogdall; Claus K Hogdall; Allan Jensen; Susanne K Kjaer; Australian Cancer Study

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, Estrid Hogdall, Claus K Hogdall, Allan Jensen, Susanne K Kjaer, Australian Cancer Study

22 Citations (Scopus)

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
Journal	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume	24
Issue number	10
Pages (from-to)	1574-84
Number of pages	11
ISSN	1055-9965
DOIs	https://doi.org/10.1158/1055-9965.epi-14-1270
Publication status	Published - 1 Oct 2015

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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., ... Australian Cancer Study (2015). Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 24(10), 1574-84. https://doi.org/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. / Kar, Siddhartha P; Tyrer, Jonathan P; Li, Qiyuan et al.

In: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Vol. 24, No. 10, 01.10.2015, p. 1574-84.

Research output: Contribution to journal › Journal article › Research › peer-review

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, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Hogdall, E , Hogdall, CK, Jensen, A, Kjaer, SK & Australian Cancer Study 2015, 'Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk', Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, vol. 24, no. 10, pp. 1574-84. https://doi.org/10.1158/1055-9965.epi-14-1270

Kar SP, Tyrer JP, Li Q, Lawrenson K, Aben KKH, Anton-Culver H et al. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2015 Oct 1;24(10):1574-84. doi: 10.1158/1055-9965.epi-14-1270

Kar, Siddhartha P ; Tyrer, Jonathan P ; Li, Qiyuan et al. / Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk. In: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2015 ; Vol. 24, No. 10. pp. 1574-84.

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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 Yu-Tang Gao and Aleksandra Gentry-Maharaj and Giles, {Graham G} and Rosalind Glasspool and Goode, {Ellen L} and Estrid Hogdall and Hogdall, {Claus K} and Allan Jensen and Kjaer, {Susanne K} and {Australian Cancer Study}",

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

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

language = "English",

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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 - Hogdall, Estrid

AU - Hogdall, Claus K

AU - Jensen, Allan

AU - Kjaer, Susanne K

AU - Australian Cancer Study

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.

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

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

M3 - Journal article

C2 - 26209509

SN - 1055-9965

VL - 24

SP - 1574

EP - 1584

JO - Cancer Epidemiology, Biomarkers & Prevention

JF - Cancer Epidemiology, Biomarkers & Prevention

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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