Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer
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Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer. / Lawrenson, Kate; Li, Qiyuan; Kar, Siddhartha; Seo, Ji-Heui; Tyrer, Jonathan; Spindler, Tassja J; Lee, Janet; Chen, Yibu; Karst, Alison; Drapkin, Ronny; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bandera, Elisa V; Bean, Yukie; Beckmann, Matthias W; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Anne; Chen, Zhihua; Cook, Linda S; Cramer, Daniel W; 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 T; Edwards, Robert P; Eilber, Ursula; Hogdall, Estrid; Hogdall, Claus; Jensen, Allan; Kruger Kjaer, Susanne; Australian Ovarian Cancer Study Group.
In: Nature Communications, Vol. 6, 8234, 09.2015.Research output: Contribution to journal › Journal article › Research › peer-review
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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
Y1 - 2015/9
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
VL - 6
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 8234
ER -
ID: 162454509