Dataset Information

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

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.

SUBMITTER: Amankwah EK

PROVIDER: S-EPMC4721602 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Amankwah Ernest K EK Lin Hui-Yi HY Tyrer Jonathan P JP Lawrenson Kate K Dennis Joe J Chornokur Ganna G Aben Katja K H KK Anton-Culver Hoda H Antonenkova Natalia N Bruinsma Fiona F Bandera Elisa V EV Bean Yukie T YT Beckmann Matthias W MW Bisogna Maria M Bjorge Line L Bogdanova Natalia N Brinton Louise A LA Brooks-Wilson Angela A Bunker Clareann H CH Butzow Ralf R Campbell Ian G IG Carty Karen K Chen Zhihua Z Chen Y Ann YA Chang-Claude Jenny J Cook Linda S LS Cramer Daniel W DW Cunningham Julie M JM Cybulski Cezary C Dansonka-Mieszkowska Agnieszka A du Bois Andreas A Despierre Evelyn E Dicks Ed E Doherty Jennifer A JA Dörk Thilo T Dürst Matthias M Easton Douglas F DF Eccles Diana M DM Edwards Robert P RP Ekici Arif B AB Fasching Peter A PA Fridley Brooke L BL Gao Yu-Tang YT Gentry-Maharaj Aleksandra A Giles Graham G GG Glasspool Rosalind R Goodman Marc T MT Gronwald Jacek J Harrington Patricia P Harter Philipp P Hasmad Hanis N HN Hein Alexander A Heitz Florian F Hildebrandt Michelle A T MA Hillemanns Peter P Hogdall Claus K CK Hogdall Estrid E Hosono Satoyo S Iversen Edwin S ES Jakubowska Anna A Jensen Allan A Ji Bu-Tian BT Karlan Beth Y BY Jim Heather H Kellar Melissa M Kiemeney Lambertus A LA Krakstad Camilla C Kjaer Susanne K SK Kupryjanczyk Jolanta J Lambrechts Diether D Lambrechts Sandrina S Le Nhu D ND Lee Alice W AW Lele Shashi S Leminen Arto A Lester Jenny J Levine Douglas A DA Liang Dong D Lim Boon Kiong BK Lissowska Jolanta J Lu Karen K Lubinski Jan J Lundvall Lene L Massuger Leon F A G LF Matsuo Keitaro K McGuire Valerie V McLaughlin John R JR McNeish Ian I Menon Usha U Milne Roger L RL Modugno Francesmary F Moysich Kirsten B KB Ness Roberta B RB Nevanlinna Heli H Eilber Ursula U Odunsi Kunle K Olson Sara H SH Orlow Irene I Orsulic Sandra S Weber Rachel Palmieri RP Paul James J Pearce Celeste L CL Pejovic Tanja T Pelttari Liisa M LM Permuth-Wey Jennifer J Pike Malcolm C MC Poole Elizabeth M EM Risch Harvey A HA Rosen Barry B Rossing Mary Anne MA Rothstein Joseph H JH Rudolph Anja A Runnebaum Ingo B IB Rzepecka Iwona K IK Salvesen Helga B HB Schernhammer Eva E Schwaab Ira I Shu Xiao-Ou XO Shvetsov Yurii B YB Siddiqui Nadeem N Sieh Weiva W Song Honglin H Southey Melissa C MC Spiewankiewicz Beata B Sucheston-Campbell Lara L Teo Soo-Hwang SH Terry Kathryn L KL Thompson Pamela J PJ Thomsen Lotte L Tangen Ingvild L IL Tworoger Shelley S SS van Altena Anne M AM Vierkant Robert A RA Vergote Ignace I Walsh Christine S CS Wang-Gohrke Shan S Wentzensen Nicolas N Whittemore Alice S AS Wicklund Kristine G KG Wilkens Lynne R LR Wu Anna H AH Wu Xifeng X Woo Yin-Ling YL Yang Hannah H Zheng Wei W Ziogas Argyrios A Kelemen Linda E LE Berchuck Andrew A Schildkraut Joellen M JM Ramus Susan J SJ Goode Ellen L EL Monteiro Alvaro N A AN Gayther Simon A SA Narod Steven A SA Pharoah Paul D P PD Sellers Thomas A TA Phelan Catherine M CM

Genetic epidemiology 20150924 8

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 ...[more]

PMID: 26399219

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Project description:In epithelial ovarian cancer (EOC), acquisition of invasiveness is accompanied by the loss of the epithelial features and the gain of a mesenchymal phenotype, a process known as epithelial-mesenchymal transition (EMT). Understanding the regulation of cell behavior during EMT is crucial for identifying the molecular mechanisms of EOC dissemination. Previously we identified the mannose receptor LY75 as the cellular phenotype modulator. LY75 suppression induces the mesenchymal to epithelial transition (MET) in EOC cell lines with mesenchymal phenotype. In this study, we used the Reduced Representation Bisulfite Sequencing (RRBS) technology for a comprehensive analysis of DNA methylation alterations during LY75-mediated EMT in EOC cells. Three different comparison (M vs E) combinations were used for RRBS analysis, as further analysis of the sequencing data based on differentially methylated regions (DMRs) covering genes’ exons and promoter regions was indicative for about 10,000 genes displaying DMRs for each of the three experimental combinations. Consecutive Venn diagram analysis of the DMRs data from the of the three experimental combinations revealed 6666 genes, displaying common altered DMRs in their exons/promoter regions, following LY75-mediated EMT alterations in EOC cells. Based on the 6666 gene list, we further proceeded with a more stringent selection of genes displaying rather high degree (>70%) of methylation in their promoter regions and previously shown to be implicated in cancer-related EMT signaling. Our stringent selection retained 45 genes (see Supplemental Table 1E), as the DNA methylation status of the promoter regions of most of these genes was further validated by an alternative approach (BSP sequencing). Ten genes were finally selected, whose promoter DNA methylation pattern coincided with their mRNA and protein expression levels. Further in vitro and in vivo studies are warranted to more completely elucidate the functional implications of these 10 genes in ovarian tumorigenesis.

Dataset Information

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

Publications

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

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