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Multicenter Study
. 2015 Oct 15;24(20):5955-64.
doi: 10.1093/hmg/ddv306. Epub 2015 Jul 30.

Shared Genetics Underlying Epidemiological Association Between Endometriosis and Ovarian Cancer

Yi Lu  1 Gabriel Cuellar-Partida  1 Jodie N Painter  2 Dale R Nyholt  3 Australian Ovarian Cancer StudyInternational Endogene Consortium (IEC)Andrew P Morris  4 Peter A Fasching  5 Alexander Hein  6 Stefanie Burghaus  6 Matthias W Beckmann  6 Diether Lambrechts  7 Els Van Nieuwenhuysen  8 Ignace Vergote  8 Adriaan Vanderstichele  8 Jennifer Anne Doherty  9 Mary Anne Rossing  10 Kristine G Wicklund  11 Jenny Chang-Claude  12 Ursula Eilber  12 Anja Rudolph  12 Shan Wang-Gohrke  13 Marc T Goodman  14 Natalia Bogdanova  15 Thilo Dörk  16 Matthias Dürst  17 Peter Hillemanns  18 Ingo B Runnebaum  17 Natalia Antonenkova  19 Ralf Butzow  20 Arto Leminen  21 Heli Nevanlinna  21 Liisa M Pelttari  21 Robert P Edwards  22 Joseph L Kelley  23 Francesmary Modugno  24 Kirsten B Moysich  25 Roberta B Ness  26 Rikki Cannioto  25 Estrid Høgdall  27 Allan Jensen  28 Graham G Giles  29 Fiona Bruinsma  30 Susanne K Kjaer  31 Michelle A T Hildebrandt  32 Dong Liang  33 Karen H Lu  34 Xifeng Wu  32 Maria Bisogna  35 Fanny Dao  35 Douglas A Levine  35 Daniel W Cramer  36 Kathryn L Terry  37 Shelley S Tworoger  38 Stacey Missmer  39 Line Bjorge  40 Helga B Salvesen  40 Reidun K Kopperud  40 Katharina Bischof  40 Katja K H Aben  41 Lambertus A Kiemeney  42 Leon F A G Massuger  43 Angela Brooks-Wilson  44 Sara H Olson  45 Valerie McGuire  46 Joseph H Rothstein  46 Weiva Sieh  46 Alice S Whittemore  46 Linda S Cook  47 Nhu D Le  48 C Blake Gilks  49 Jacek Gronwald  50 Anna Jakubowska  50 Jan Lubiński  50 Jan Gawełko  51 Honglin Song  52 Jonathan P Tyrer  52 Nicolas Wentzensen  53 Louise Brinton  53 Britton Trabert  53 Jolanta Lissowska  54 John R Mclaughlin  55 Steven A Narod  56 Catherine Phelan  57 Hoda Anton-Culver  58 Argyrios Ziogas  32 Diana Eccles  59 Simon A Gayther  60 Aleksandra Gentry-Maharaj  61 Usha Menon  61 Susan J Ramus  60 Anna H Wu  60 Agnieszka Dansonka-Mieszkowska  62 Jolanta Kupryjanczyk  62 Agnieszka Timorek  63 Lukasz Szafron  62 Julie M Cunningham  64 Brooke L Fridley  65 Stacey J Winham  66 Elisa V Bandera  67 Elizabeth M Poole  38 Terry K Morgan  68 Harvey A Risch  69 Ellen L Goode  70 Joellen M Schildkraut  71 Penelope M Webb  72 Celeste L Pearce  73 Andrew Berchuck  74 Paul D P Pharoah  75 Grant W Montgomery  76 Krina T Zondervan  77 Georgia Chenevix-Trench  78 Stuart MacGregor  79
Collaborators, Affiliations
Free PMC article
Multicenter Study

Shared Genetics Underlying Epidemiological Association Between Endometriosis and Ovarian Cancer

Yi Lu et al. Hum Mol Genet. .
Free PMC article

Abstract

Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07-0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.

Figures

Figure 1.
Figure 1.
Genetic risk prediction between endometriosis and EOC histotypes [serous, high-grade and low-grade serous (denoted as “Srs High-grade” and “Srs Low-grade” respectively), mucinous, endometrioid and clear cell]. (A) EOC histotypes as discovery and endometriosis as target; (B) endometriosis as discovery and EOC histotypes as target; and (C) endometriosis as discovery and EOC histotypes as target, after the exclusion of women with endometriosis in the ovarian cancer case–control set. The figures show the association (y-axis: −log10P) between genetic risk scores calculated from the discovery set and the target disease. The shading denotes the P-value bins used to select SNPs from the discovery set. The dashed horizontal line marks the significance threshold (P = 0.05). The genetic risk scores were calculated from all platform-overlapping SNPs without LD clumping.

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