Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer Journal Article
| Authors: | Lawrenson, K.; Li, Q.; Kar, S.; Seo, J.; Tyrer, J.; Spindler, T.; Lee, J.; Chen, Y.; Karst, A.; Draphkin, R.; Aben, K. K. H.; Anton-Culver, H.; Antonenkova, N.; Australian Ovarian Cancer Study Group; Baker, H.; Bandera, E. V.; Bean, Y.; Beckmann, M. W.; Berchuck, A.; Bisogna, M.; Bjorge, L.; Bodfanova, N.; Brinton, L. A.; Brooks-Wilson, A.; Bruinsma, F.; Butzow, R.; Campbell, I. G.; Carty, K.; Chang-Claude, J.; Chenevix-Trench, G.; Chen, A.; Chen, Z.; Cook, L. S.; Cramer, D. W.; Dicks, E.; Doherty, J. A.; Dork, T.; du Bois, A.; Durst, M.; Eccles, D.; Easton, D. T.; Edwards, R. P.; Eilber, U.; Ekici, A. B.; Fasching, P. A.; Fridley, B. L.; Gao, Y. T.; Gentry-Maharaj, A.; Giles, G. G.; Glasspool, R.; Goode, E. L.; Goodman, M. T.; Grownwald, J.; Harrington, P.; Harter, P.; Hasmad, H. N.; Hein, A.; Heitz, F.; Hildebrandt, M. A. T.; Hillemanns, P.; Hogdall, E.; Hogdall, C.; Hosono, S.; Iversen, E. S.; Jakubowska, A.; James, P.; Jensen, A.; Ji, B. T.; Karlan, B. Y.; Kjaer, S. K.; Keleman, L. E.; Kellar, M.; Kelley, J. L.; Kiemeney, L. A.; Krakstad, C.; Kupryjanczyk, J.; Lambrechts, D.; Lambrechts, S.; Le, N. D.; Lee, A. W.; Lele, S.; Leminen, A.; Lester, J.; Levine, D. A.; Liang, D.; Lissowska, J.; Lu, K.; Lubninski, J.; Lundvall, L.; Massuger, L. F. A. G.; Matsuo, K.; McGuire, V.; McLaughlin, J. R.; Nevanlinna, H.; McNeish, I.; Menon, U.; Modugno, F.; Moysich, K. B.; Narod, S. A.; Nedergaard, L.; Ness, R. B.; Azmi, M. A. N.; Odunsi, K.; Olson, S. H.; Orlow, I.; Orsulic, S.; Palmieri Weber, R.; Pearce, C. L.; Pejovic, T.; Pelttari, L. M.; Permuth-Wey, J.; Phelan, C. M.; Pike, M. C.; Poole, E. M.; Ramus, S. J.; Risch, H. A.; Rosen, B.; Rossing, M. A.; Rothstein, J. H.; Rudolph, A.; Runnebaum, I. B.; Rzepecka, I. K.; Salvesen, H. B.; Schildkraut, J. M.; Schwaab, I.; Seller, T. A.; Shu, X. O.; Shvestsov, Y. B.; Siddiqui, N.; Sieh, W.; Song, H.; Southey, M. C.; Sucheston, L.; Tangen, I. L.; Teo, S. H.; Terry, K. L.; Thompson, P. J.; Timorek, A.; Tsai, Y. Y.; Tworoger, S. S.; van Altena, A. M.; Van Nieuwenhuysen, E.; Vergote, I.; Vierkant, R. A.; Wang-Gohrke, S.; Walsh, C.; Wentzensen, N.; Whittemore, A. S.; Wicklund, K. G.; Wilkens, L. R.; Woo, Y. L.; Wu, X.; Wu, A. H.; Yang, H.; Zheng, W.; Ziogas, A.; Monteiro, A.; Pharoah, P. D.; Gayther, S. A.; Freedman, M. L. |
| Article 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. © 2015 Macmillan Publishers Limited. All rights reserved. |
| Keywords: | human cell; promoter region; single nucleotide polymorphism; nonhuman; cancer grading; genetic analysis; chromosome; gene overexpression; gene expression; protein; genetic association; genetic variability; transcriptomics; rna; genetic susceptibility; cancer stem cell; ovary carcinoma; genomics; genetic risk; anchorage independent growth; quantitative trait locus; womens health; chromosome 1p; chromosome 2q; cells and cell components; cancer; human; female; article; hoxd9 gene |
| Journal Title: | Nature Communications |
| Volume: | 6 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2015-09-22 |
| Start Page: | 8234 |
| Language: | English |
| DOI: | 10.1038/ncomms9234 |
| PROVIDER: | scopus |
| PMCID: | PMC4580986 |
| PUBMED: | 26391404 |
| DOI/URL: | |
| Notes: | Export Date: 2 November 2015 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work