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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 KH;
- 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;
- Ekici, Arif B;
- Fasching, Peter A;
- Fridley, Brooke L;
- Gao, Yu-Tang;
- Gentry-Maharaj, Aleksandra;
- Giles, Graham G;
- Glasspool, Rosalind;
- Goode, Ellen L;
- Goodman, Marc T;
- Grownwald, Jacek;
- Harrington, Patricia;
- Harter, Philipp;
- Hasmad, Hanis Nazihah;
- Hein, Alexander;
- Heitz, Florian;
- Hildebrandt, Michelle AT;
- Hillemanns, Peter;
- Hogdall, Estrid;
- Hogdall, Claus;
- Hosono, Satoyo;
- Iversen, Edwin S;
- Jakubowska, Anna;
- James, Paul;
- Jensen, Allan;
- Ji, Bu-Tian;
- Karlan, Beth Y;
- Kruger Kjaer, Susanne;
- Kelemen, Linda E;
- Kellar, Melissa;
- Kelley, Joseph L;
- 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 FAG;
- Matsuo, Keitaro;
- McGuire, Valerie;
- McLaughlin, John R;
- Nevanlinna, Heli;
- McNeish, Ian;
- Menon, Usha;
- Modugno, Francesmary;
- Moysich, Kirsten B;
- Narod, Steven A;
- Nedergaard, Lotte;
- Ness, Roberta B;
- Azmi, Mat Adenan Noor;
- Odunsi, Kunle;
- Olson, Sara H;
- Orlow, Irene;
- Orsulic, Sandra;
- Weber, Rachel Palmieri;
- Pearce, Celeste L;
- 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 B;
- Schildkraut, Joellen M;
- Schwaab, Ira;
- Sellers, Thomas A;
- Shu, Xiao-Ou;
- Shvetsov, Yurii B;
- Siddiqui, Nadeem;
- Sieh, Weiva;
- Song, Honglin;
- Southey, Melissa C;
- Sucheston, Lara;
- Tangen, Ingvild L;
- Teo, Soo-Hwang;
- Terry, Kathryn L;
- Thompson, Pamela J;
- Timorek, Agnieszka;
- Tsai, Ya-Yu;
- Tworoger, Shelley S;
- van Altena, Anne M;
- Van Nieuwenhuysen, Els;
- Vergote, Ignace;
- Vierkant, Robert A;
- Wang-Gohrke, Shan;
- Walsh, Christine;
- Wentzensen, Nicolas;
- Whittemore, Alice S;
- Wicklund, Kristine G;
- Wilkens, Lynne R;
- Woo, Yin-Ling;
- Wu, Xifeng;
- Wu, Anna H;
- Yang, Hannah;
- Zheng, Wei;
- Ziogas, Argyrios;
- Monteiro, Alvaro;
- Pharoah, Paul D;
- Gayther, Simon A;
- Freedman, Matthew L
- et al.
Published Web Location
https://doi.org/10.1038/ncomms9234Abstract
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.
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