Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

1] Department of Cancer Epidemiology, Division of Population Sciences, Moffitt Cancer Center, Tampa, Florida CB1 8RN, USA [2].
Nature Communications (Impact Factor: 11.47). 03/2013; 4:1627. DOI: 10.1038/ncomms2613
Source: PubMed


Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.

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Available from: Keitaro Matsuo, Jan 30, 2014
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    • "The most common ovarian cancer is invasive epithelial ovarian cancer, with five common histological subtypes: high grade serous (70%), endometrioid (10%), clear cell (10%), low grade serous (5%), and mucinous (3%). A family history of breast or ovarian cancer in first degree relatives increases the risk for ovarian cancer2; family-based studies have revealed high- and moderate-penetrance genes including BRCA13, BRCA24, DNA mismatch repair genes5, RAD51C67, RAD51D8 and BRIP16, and case-control studies have identified eleven common variants associating with modestly increased risks9101112131415. Estimates of the contribution of germline BRCA1 and BRCA2 mutations to EOC vary widely from 5% to 20%16; somatic mutations in BRCA1 and BRCA2 occur less frequently (in 2%–8% patients)1718 and, as has BRCA1 methylation19202122 have been reported in ovarian cancer patients with no family history23. "
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    ABSTRACT: We evaluated homologous recombination deficient (HRD) phenotypes in epithelial ovarian cancer (EOC) considering BRCA1, BRCA2, and RAD51C in a large well-annotated patient set. We evaluated EOC patients for germline deleterious mutations (n = 899), somatic mutations (n = 279) and epigenetic alterations (n = 482) in these genes using NGS and genome-wide methylation arrays. Deleterious germline mutations were identified in 32 (3.6%) patients for BRCA1, in 28 (3.1%) for BRCA2 and in 26 (2.9%) for RAD51C. Ten somatically sequenced patients had deleterious alterations, six (2.1%) in BRCA1 and four (1.4%) in BRCA2. Fifty two patients (10.8%) had methylated BRCA1 or RAD51C. HRD patients with germline or somatic alterations in any gene were more likely to be high grade serous, have an earlier diagnosis age and have ovarian and/or breast cancer family history. The HRD phenotype was most common in high grade serous EOC. Identification of EOC patients with an HRD phenotype may help tailor specific therapies.
    Scientific Reports 02/2014; 4:4026. DOI:10.1038/srep04026 · 5.58 Impact Factor
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    • "Indeed, integrative genomics studies of other cancers, for example prostate cancer, indicate that the tumor epigenetic landscape is partly mediated by genetic differences, which may affect disease progression [17,18]. Additionally, Genome-wide association studies (GWAS) in the context of ovarian cancer have identified 11 common risk alleles [7,19-24], and six of these are located in homeobox gene clusters (HOXA, HOXB, and HOXD), homeobox-related genes (HNF1B), or genes expressed in early progenitor cells (BNC2, TERT) [20,25,26]; many developmental genes such as these are silenced by DNAm in differentiated cells and become aberrantly hypomethylated during tumorigenesis [26]. "
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    BMC Medical Genomics 01/2014; 7(1):8. DOI:10.1186/1755-8794-7-8 · 2.87 Impact Factor
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    ABSTRACT: Fallopian tube secretory epithelial cells (FTSECs) have been implicated as a cell-of-origin for high-grade serous epithelial ovarian cancer. However, there are relatively few in vitro models of this tissue type available for use in studies of FTSEC biology and malignant transformation. In vitro three-dimensional (3D) cell culture models aim to recreate the architecture and geometry of tissues in vivo and restore the complex network of cell-cell/cell-matrix interactions that occur throughout the surface of the cell membrane. We have established and characterized 3D spheroid culture models of primary FTSECs. FTSEC spheroids contain central cores of hyaline matrix surrounded by mono- or multi-layer epithelial sheets. We found that 3D culturing alters the molecular characteristics of FTSECs compared to 2D cultures of the same cells. Gene expression profiling identified more than a thousand differentially expressed genes between 3D and 2D cultures of the same FTSEC lines. Pathways significantly under-represented in 3D FTSEC cultures were associated with cell cycle progression and DNA replication. This was also reflected in the reduced proliferative indices observed in 3D spheroids stained for the proliferation marker MIB1. Comparisons with gene expression profiles of fresh fallopian tube tissues revealed that 2D FTSEC cultures clustered with follicular phase tubal epithelium, whereas 3D FTSEC cultures clustered with luteal phase samples. This 3D model of fallopian tube secretory epithelial cells will advance our ability to study the underlying biology and etiology of fallopian tube tissues and the pathogenesis of high-grade serous epithelial ovarian cancer.
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