Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

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

N1 - ©2015 American Association for Cancer Research.

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 : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

JF - Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

IS - 10

ER -