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. 2015 Dec;39(8):689-97.
doi: 10.1002/gepi.21921. Epub 2015 Sep 24.

Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

Ernest K Amankwah  1   2 , Hui-Yi Lin  3 , Jonathan P Tyrer  4 , Kate Lawrenson  5 , Joe Dennis  4 , Ganna Chornokur  1 , Katja K H Aben  6   7 , Hoda Anton-Culver  8 , Natalia Antonenkova  9 , Fiona Bruinsma  10 , Elisa V Bandera  11 , Yukie T Bean  12   13 , Matthias W Beckmann  14 , Maria Bisogna  15 , Line Bjorge  16   17 , Natalia Bogdanova  18 , Louise A Brinton  19 , Angela Brooks-Wilson  20   21 , Clareann H Bunker  22 , Ralf Butzow  23   24 , Ian G Campbell  25   26   27 , Karen Carty  28   29 , Zhihua Chen  3 , Y Ann Chen  3 , Jenny Chang-Claude  30 , Linda S Cook  31 , Daniel W Cramer  32 , Julie M Cunningham  33 , Cezary Cybulski  34 , Agnieszka Dansonka-Mieszkowska  35 , Andreas du Bois  36   37 , Evelyn Despierre  38 , Ed Dicks  39 , Jennifer A Doherty  40   41 , Thilo Dörk  18 , Matthias Dürst  42 , Douglas F Easton  43   44 , Diana M Eccles  45 , Robert P Edwards  46 , Arif B Ekici  47 , Peter A Fasching  14   48 , Brooke L Fridley  49 , Yu-Tang Gao  50 , Aleksandra Gentry-Maharaj  51 , Graham G Giles  10   52 , Rosalind Glasspool  29 , Marc T Goodman  53   54 , Jacek Gronwald  34 , Patricia Harrington  39 , Philipp Harter  36   37 , Hanis N Hasmad  55 , Alexander Hein  14 , Florian Heitz  36   37 , Michelle A T Hildebrandt  56 , Peter Hillemanns  18 , Claus K Hogdall  57 , Estrid Hogdall  58   59 , Satoyo Hosono  60 , Edwin S Iversen  61 , Anna Jakubowska  34 , Allan Jensen  58 , Bu-Tian Ji  19 , Beth Y Karlan  62 , Heather Jim  63 , Melissa Kellar  12   13 , Lambertus A Kiemeney  6 , Camilla Krakstad  16   17 , Susanne K Kjaer  57   58 , Jolanta Kupryjanczyk  35 , Diether Lambrechts  64   65 , Sandrina Lambrechts  38 , Nhu D Le  66 , Alice W Lee  5 , Shashi Lele  67 , Arto Leminen  23 , Jenny Lester  62 , Douglas A Levine  15 , Dong Liang  68 , Boon Kiong Lim  69 , Jolanta Lissowska  70 , Karen Lu  71 , Jan Lubinski  34 , Lene Lundvall  57 , Leon F A G Massuger  72 , Keitaro Matsuo  60 , Valerie McGuire  73 , John R McLaughlin  74 , Ian McNeish  29 , Usha Menon  51 , Roger L Milne  10   52 , Francesmary Modugno  22   75   76 , Kirsten B Moysich  67 , Roberta B Ness  77 , Heli Nevanlinna  23 , Ursula Eilber  30 , Kunle Odunsi  78 , Sara H Olson  79 , Irene Orlow  79 , Sandra Orsulic  62 , Rachel Palmieri Weber  80 , James Paul  29 , Celeste L Pearce  5   81 , Tanja Pejovic  12   13 , Liisa M Pelttari  23 , Jennifer Permuth-Wey  1 , Malcolm C Pike  5   79 , Elizabeth M Poole  82   83 , Harvey A Risch  84 , Barry Rosen  85   86 , Mary Anne Rossing  41 , Joseph H Rothstein  73 , Anja Rudolph  30 , Ingo B Runnebaum  42 , Iwona K Rzepecka  35 , Helga B Salvesen  16   17 , Eva Schernhammer  82   83 , Ira Schwaab  87 , Xiao-Ou Shu  88 , Yurii B Shvetsov  89 , Nadeem Siddiqui  28 , Weiva Sieh  73 , Honglin Song  39 , Melissa C Southey  26 , Beata Spiewankiewicz  90 , Lara Sucheston-Campbell  67 , Soo-Hwang Teo  55   91 , Kathryn L Terry  32   83 , Pamela J Thompson  53   54 , Lotte Thomsen  92 , Ingvild L Tangen  16   17 , Shelley S Tworoger  32   83 , Anne M van Altena  72 , Robert A Vierkant  93 , Ignace Vergote  38 , Christine S Walsh  62 , Shan Wang-Gohrke  30 , Nicolas Wentzensen  19 , Alice S Whittemore  73 , Kristine G Wicklund  41 , Lynne R Wilkens  89 , Anna H Wu  5 , Xifeng Wu  56 , Yin-Ling Woo  69 , Hannah Yang  19 , Wei Zheng  94 , Argyrios Ziogas  8 , Linda E Kelemen  95 , Andrew Berchuck  96 ; Georgia Chenevix-Trench on behalf of the AOCS management group; Joellen M Schildkraut  97 , Susan J Ramus  5 , Ellen L Goode  98 , Alvaro N A Monteiro  3 , Simon A Gayther  5 , Steven A Narod  99 , Paul D P Pharoah  43 , Thomas A Sellers  1 , Catherine M Phelan  1
Affiliations

Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

Ernest K Amankwah et al. Genet Epidemiol. 2015 Dec.

Abstract

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.

Keywords: epithelial-mesenchymal transition; ovarian cancer; single-nucleotide polymorphisms.

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Conflict of interest statement

The co-authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1. Annotation of regulatory elements at rs3771044
This variant lies within a super-enhancer detected in ovarian tissues (data from Hsinz et al). Using data from ENCODE Regulation tracks, we identified evidence of cell type specific H3K4me1 marks. This SNP also coincides with ChIPseq marks for multiple transactions factors (TFs) including EP300, NFKB and RUNX3. This variant lies with a DNasel hypersensitive region detected in 109 samples.
See this image and copyright information in PMC

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