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

Publication ,  Journal Article
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; Baker, H ...
Published in: Nat Commun
September 22, 2015

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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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

September 22, 2015

Volume

6

Start / End Page

8234

Location

England

Related Subject Headings

  • Quantitative Trait Loci
  • Protein Binding
  • Ovarian Neoplasms
  • Nuchal Cord
  • Neoplasms, Glandular and Epithelial
  • Neoplasm Proteins
  • Humans
  • Homeodomain Proteins
  • Genetic Predisposition to Disease
  • Genetic Association Studies
 

Citation

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Lawrenson, K., Li, Q., Kar, S., Seo, J.-H., Tyrer, J., Spindler, T. J., … Freedman, M. L. (2015). Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer. Nat Commun, 6, 8234. https://doi.org/10.1038/ncomms9234
Lawrenson, Kate, Qiyuan Li, Siddhartha Kar, Ji-Heui Seo, Jonathan Tyrer, Tassja J. Spindler, Janet Lee, et al. “Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.Nat Commun 6 (September 22, 2015): 8234. https://doi.org/10.1038/ncomms9234.
Lawrenson K, Li Q, Kar S, Seo J-H, Tyrer J, Spindler TJ, et al. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer. Nat Commun. 2015 Sep 22;6:8234.
Lawrenson, Kate, et al. “Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.Nat Commun, vol. 6, Sept. 2015, p. 8234. Pubmed, doi: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, Australian Ovarian Cancer Study Group, 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, Ekici AB, Fasching PA, Fridley BL, Gao Y-T, Gentry-Maharaj A, Giles GG, Glasspool R, Goode EL, Goodman MT, Grownwald J, Harrington P, Harter P, Hasmad HN, Hein A, Heitz F, Hildebrandt MAT, Hillemanns P, Hogdall E, Hogdall C, Hosono S, Iversen ES, Jakubowska A, James P, Jensen A, Ji B-T, Karlan BY, Kruger Kjaer S, Kelemen LE, Kellar M, Kelley JL, Kiemeney LA, Krakstad C, Kupryjanczyk J, Lambrechts D, Lambrechts S, Le ND, Lee AW, Lele S, Leminen A, Lester J, Levine DA, Liang D, Lissowska J, Lu K, Lubinski J, Lundvall L, Massuger LFAG, Matsuo K, McGuire V, McLaughlin JR, Nevanlinna H, McNeish I, Menon U, Modugno F, Moysich KB, Narod SA, Nedergaard L, Ness RB, Azmi MAN, Odunsi K, Olson SH, Orlow I, Orsulic S, Weber RP, Pearce CL, Pejovic T, Pelttari LM, Permuth-Wey J, Phelan CM, Pike MC, Poole EM, Ramus SJ, Risch HA, Rosen B, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Rzepecka IK, Salvesen HB, Schildkraut JM, Schwaab I, Sellers TA, Shu X-O, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Sucheston L, Tangen IL, Teo S-H, Terry KL, Thompson PJ, Timorek A, Tsai Y-Y, Tworoger SS, van Altena AM, Van Nieuwenhuysen E, Vergote I, Vierkant RA, Wang-Gohrke S, Walsh C, Wentzensen N, Whittemore AS, Wicklund KG, Wilkens LR, Woo Y-L, Wu X, Wu AH, Yang H, Zheng W, Ziogas A, Monteiro A, Pharoah PD, Gayther SA, Freedman ML. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer. Nat Commun. 2015 Sep 22;6:8234.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

September 22, 2015

Volume

6

Start / End Page

8234

Location

England

Related Subject Headings

  • Quantitative Trait Loci
  • Protein Binding
  • Ovarian Neoplasms
  • Nuchal Cord
  • Neoplasms, Glandular and Epithelial
  • Neoplasm Proteins
  • Humans
  • Homeodomain Proteins
  • Genetic Predisposition to Disease
  • Genetic Association Studies