Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Kate Lawrenson; Qiyuan Li; Siddhartha Kar; Ji-Heui Seo; Jonathan Tyrer; Tassja J Spindler; Janet Lee; Yibu Chen; Alison Karst; Ronny Drapkin; Katja K H Aben; Hoda Anton-Culver; Natalia Antonenkova; Helen Baker; Elisa V Bandera; Yukie Bean; Matthias W Beckmann; Andrew Berchuck; Maria Bisogna; Line Bjorge; Natalia Bogdanova; Louise A Brinton; Angela Brooks-Wilson; Fiona Bruinsma; Ralf Butzow; Ian G Campbell; Karen Carty; Jenny Chang-Claude; Georgia Chenevix-Trench; Anne Chen; Zhihua Chen; Linda S Cook; Daniel W 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 T Easton; Robert P Edwards; Ursula Eilber; Estrid Hogdall; Claus Hogdall; Allan Jensen; Susanne Kruger Kjaer; Australian Ovarian Cancer Study Group

doi:10.1038/ncomms9234

Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Kate Lawrenson, Qiyuan Li, Siddhartha Kar, Ji-Heui Seo, Jonathan Tyrer, Tassja J Spindler, Janet Lee, Yibu Chen, Alison Karst, Ronny Drapkin, Katja K H Aben, Hoda Anton-Culver, Natalia Antonenkova, Helen Baker, Elisa V Bandera, Yukie Bean, Matthias W Beckmann, Andrew Berchuck, Maria Bisogna, Line BjorgeNatalia Bogdanova, Louise A Brinton, Angela Brooks-Wilson, Fiona Bruinsma, Ralf Butzow, Ian G Campbell, Karen Carty, Jenny Chang-Claude, Georgia Chenevix-Trench, Anne Chen, Zhihua Chen, Linda S Cook, Daniel W 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 T Easton, Robert P Edwards, Ursula Eilber, Estrid Hogdall, Claus Hogdall, Allan Jensen, Susanne Kruger Kjaer, Australian Ovarian Cancer Study Group

31 Citationer (Scopus)

Abstract

Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10^-5). For three cis-eQTL associations (P<1.4 × 10^-3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10^-10 for risk variants (P<10^-4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.

Originalsprog	Engelsk
Artikelnummer	8234
Tidsskrift	Nature Communications
Vol/bind	6
Antal sider	14
ISSN	2041-1723
DOI	https://doi.org/10.1038/ncomms9234
Status	Udgivet - 22 sep. 2015

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10.1038/ncomms9234Licens: CC BY

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Lawrenson, K., Li, Q., Kar, S., Seo, J-H., Tyrer, J., Spindler, T. J., Lee, J., Chen, Y., Karst, A., Drapkin, R., Aben, K. K. H., Anton-Culver, H., Antonenkova, N., Baker, H., Bandera, E. V., Bean, Y., Beckmann, M. W., Berchuck, A., Bisogna, M., ... Australian Ovarian Cancer Study Group (2015). Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer. Nature Communications, 6, [8234]. https://doi.org/10.1038/ncomms9234

Lawrenson, K, Li, Q, Kar, S, Seo, J-H, Tyrer, J, Spindler, TJ, Lee, J, Chen, Y, Karst, A, Drapkin, R, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bandera, EV, Bean, Y, Beckmann, MW, Berchuck, A, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chenevix-Trench, G, Chen, A, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, du Bois, A, Dürst, M, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Hogdall, E , Hogdall, C, Jensen, A, Kruger Kjaer, S & Australian Ovarian Cancer Study Group 2015, 'Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer', Nature Communications, bind 6, 8234. https://doi.org/10.1038/ncomms9234

@article{2c2a1b7f052246a8920bd4b5fa4fda3d,

title = "Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer",

abstract = "Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10-5). For three cis-eQTL associations (P<1.4 × 10-3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10-10 for risk variants (P<10-4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.",

keywords = "Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Predisposition to Disease, Homeodomain Proteins, Humans, Neoplasm Proteins, Neoplasms, Glandular and Epithelial, Nuchal Cord, Ovarian Neoplasms, Protein Binding, Quantitative Trait Loci",

author = "Kate Lawrenson and Qiyuan Li and Siddhartha Kar and Ji-Heui Seo and Jonathan Tyrer and Spindler, {Tassja J} and Janet Lee and Yibu Chen and Alison Karst and Ronny Drapkin and Aben, {Katja K H} and Hoda Anton-Culver and Natalia Antonenkova and Helen Baker and Bandera, {Elisa V} and Yukie Bean and Beckmann, {Matthias W} and Andrew Berchuck and Maria Bisogna and Line Bjorge and Natalia Bogdanova and Brinton, {Louise A} and Angela Brooks-Wilson and Fiona Bruinsma and Ralf Butzow and Campbell, {Ian G} and Karen Carty and Jenny Chang-Claude and Georgia Chenevix-Trench and Anne Chen and Zhihua Chen and Cook, {Linda S} and Cramer, {Daniel W} 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 T} and Edwards, {Robert P} and Ursula Eilber and Estrid Hogdall and Claus Hogdall and Allan Jensen and {Kruger Kjaer}, Susanne and {Australian Ovarian Cancer Study Group}",

year = "2015",

month = sep,

day = "22",

doi = "10.1038/ncomms9234",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

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TY - JOUR

T1 - Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

AU - Lawrenson, Kate

AU - Li, Qiyuan

AU - Kar, Siddhartha

AU - Seo, Ji-Heui

AU - Tyrer, Jonathan

AU - Spindler, Tassja J

AU - Lee, Janet

AU - Chen, Yibu

AU - Karst, Alison

AU - Drapkin, Ronny

AU - Aben, Katja K H

AU - Anton-Culver, Hoda

AU - Antonenkova, Natalia

AU - Baker, Helen

AU - Bandera, Elisa V

AU - Bean, Yukie

AU - Beckmann, Matthias W

AU - Berchuck, Andrew

AU - Bisogna, Maria

AU - Bjorge, Line

AU - Bogdanova, Natalia

AU - Brinton, Louise A

AU - Brooks-Wilson, Angela

AU - Bruinsma, Fiona

AU - Butzow, Ralf

AU - Campbell, Ian G

AU - Carty, Karen

AU - Chang-Claude, Jenny

AU - Chenevix-Trench, Georgia

AU - Chen, Anne

AU - Chen, Zhihua

AU - Cook, Linda S

AU - Cramer, Daniel W

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 T

AU - Edwards, Robert P

AU - Eilber, Ursula

AU - Hogdall, Estrid

AU - Hogdall, Claus

AU - Jensen, Allan

AU - Kruger Kjaer, Susanne

AU - Australian Ovarian Cancer Study Group

PY - 2015/9/22

Y1 - 2015/9/22

N2 - Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10-5). For three cis-eQTL associations (P<1.4 × 10-3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10-10 for risk variants (P<10-4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.

AB - Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10-5). For three cis-eQTL associations (P<1.4 × 10-3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10-10 for risk variants (P<10-4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.

KW - Cell Line, Tumor

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Homeodomain Proteins

KW - Humans

KW - Neoplasm Proteins

KW - Neoplasms, Glandular and Epithelial

KW - Nuchal Cord

KW - Ovarian Neoplasms

KW - Protein Binding

KW - Quantitative Trait Loci

U2 - 10.1038/ncomms9234

DO - 10.1038/ncomms9234

M3 - Journal article

C2 - 26391404

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 8234

ER -

Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Abstract

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