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. 2017 Feb 14;116(4):524-535.
doi: 10.1038/bjc.2016.426. Epub 2017 Jan 19.

Enrichment of Putative PAX8 Target Genes at Serous Epithelial Ovarian Cancer Susceptibility Loci

Siddhartha P Kar  1 Emily Adler  2 Jonathan Tyrer  1   3 Dennis Hazelett  4   5 Hoda Anton-Culver  6 Elisa V Bandera  7 Matthias W Beckmann  8 Andrew Berchuck  9 Natalia Bogdanova  10 Louise Brinton  11 Ralf Butzow  12 Ian Campbell  13   14 Karen Carty  15 Jenny Chang-Claude  16   17 Linda S Cook  18 Daniel W Cramer  19 Julie M Cunningham  20 Agnieszka Dansonka-Mieszkowska  21 Jennifer Anne Doherty  22 Thilo Dörk  23 Matthias Dürst  24 Diana Eccles  25 Peter A Fasching  8   26 James Flanagan  27 Aleksandra Gentry-Maharaj  28 Rosalind Glasspool  15 Ellen L Goode  29 Marc T Goodman  30   31 Jacek Gronwald  32 Florian Heitz  33   34 Michelle A T Hildebrandt  35 Estrid Høgdall  36   37 Claus K Høgdall  38 David G Huntsman  39   40   41 Allan Jensen  36 Beth Y Karlan  42 Linda E Kelemen  43 Lambertus A Kiemeney  44 Susanne K Kjaer  36   45 Jolanta Kupryjanczyk  21 Diether Lambrechts  46   47 Douglas A Levine  48 Qiyuan Li  49   50 Jolanta Lissowska  51 Karen H Lu  52 Jan Lubiński  32 Leon F A G Massuger  53 Valerie McGuire  54 Iain McNeish  55 Usha Menon  28 Francesmary Modugno  56   57   58 Alvaro N Monteiro  59 Kirsten B Moysich  60 Roberta B Ness  61 Heli Nevanlinna  62 James Paul  15 Celeste L Pearce  2   63 Tanja Pejovic  64   65 Jennifer B Permuth  59 Catherine Phelan  59 Malcolm C Pike  2   66 Elizabeth M Poole  67 Susan J Ramus  68 Harvey A Risch  69 Mary Anne Rossing  70   71 Helga B Salvesen  72   73 Joellen M Schildkraut  74   75 Thomas A Sellers  59 Mark Sherman  11 Nadeem Siddiqui  76 Weiva Sieh  54 Honglin Song  3 Melissa Southey  77 Kathryn L Terry  19   78 Shelley S Tworoger  67   78 Christine Walsh  42 Nicolas Wentzensen  11 Alice S Whittemore  54 Anna H Wu  2 Hannah Yang  11 Wei Zheng  79 Argyrios Ziogas  80 Matthew L Freedman  81   82 Simon A Gayther  5   83 Paul D P Pharoah  1   3 Kate Lawrenson  5   84
Affiliations
Free PMC article

Enrichment of Putative PAX8 Target Genes at Serous Epithelial Ovarian Cancer Susceptibility Loci

Siddhartha P Kar et al. Br J Cancer. .
Free PMC article

Abstract

Background: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis.

Methods: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals).

Results: The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10-5 (including six with P<5 × 10-8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation.

Conclusions: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.

Conflict of interest statement

The authors declare no conflict of interest.

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