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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:BackgroundDefective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.MethodsIn total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.ResultsThe most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4).ConclusionThese results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.

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.

Project description:Purpose: Circular RNAs (circRNAs) have been reported to regulate the incidence of tumor by regulating the transcriptional level and post-transcriptional level of tumor-related genes, and are significantly correlated with tumor metastasis and progression. CircRNA_100395 (circ_100395) has been reported to suppress lung cancer cell proliferation, and might act as an oncogene in deveopment of various cancers. However, the expression and function of circ_100395 in ovarian cancer has not been systematically researched. Methods: The expression of circ_100395 in ovarian cancer tissues was detected by Real-time Quantitative polymerase chain reaction (RT-qPCR), while the relationship between circ_100395 expression and clinicopathological characteristics was further analyzed. After increasing the expression of circ_100395 by plasmid transfection in ovarian cancer cells, we further investigated the cell proliferation, invasion and migration by cell counting kit-8 (CCK-8), and Transwell assays. Epithelial-mesenchymal transition (EMT) pathway was also measured by western blotting. In addition, the relationship among circ_100395, miR-1228 and p53 in ovarian cancer, was explored by luciferase reporter assay. Results: The expression of circ_100395 was found to be significantly down-regulated in ovarian cancer, while low expression of circ_100395 was highly correlated with the poor outcomes. In addition, upregulation of circ_100395 could significantly inhibit tumor growth, metastasis and EMT signaling pathway in ovarian cancer. Furthermore, the expression level of circ_100395 was negatively correlated with the expression of miR-1228, and with the addition of miR-1228 could reverse anti-cell proliferation effect induced by circ_100395 in ovarian cancer cells. In addition, p53 might be the key target of circ_100395 / miR-1228 axis in ovarian cancer. Conclusion: CircRNA_100395 could inhibit cell growth and metastasis of ovarian cancer cells via regulating the miR-1228/p53/EMT axis.

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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