13 research outputs found

    Differential Analysis of Ovarian and Endometrial Cancers Identifies a Methylator Phenotype

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    Despite improved outcomes in the past 30 years, less than half of all women diagnosed with epithelial ovarian cancer live five years beyond their diagnosis. Although typically treated as a single disease, epithelial ovarian cancer includes several distinct histological subtypes, such as papillary serous and endometrioid carcinomas. To address whether the morphological differences seen in these carcinomas represent distinct characteristics at the molecular level we analyzed DNA methylation patterns in 11 papillary serous tumors, 9 endometrioid ovarian tumors, 4 normal fallopian tube samples and 6 normal endometrial tissues, plus 8 normal fallopian tube and 4 serous samples from TCGA. For comparison within the endometrioid subtype we added 6 primary uterine endometrioid tumors and 5 endometrioid metastases from uterus to ovary. Data was obtained from 27,578 CpG dinucleotides occurring in or near promoter regions of 14,495 genes. We identified 36 locations with significant increases or decreases in methylation in comparisons of serous tumors and normal fallopian tube samples. Moreover, unsupervised clustering techniques applied to all samples showed three major profiles comprising mostly normal samples, serous tumors, and endometrioid tumors including ovarian, uterine and metastatic origins. The clustering analysis identified 60 differentially methylated sites between the serous group and the normal group. An unrelated set of 25 serous tumors validated the reproducibility of the methylation patterns. In contrast, >1,000 genes were differentially methylated between endometrioid tumors and normal samples. This finding is consistent with a generalized regulatory disruption caused by a methylator phenotype. Through DNA methylation analyses we have identified genes with known roles in ovarian carcinoma etiology, whereas pathway analyses provided biological insight to the role of novel genes. Our finding of differences between serous and endometrioid ovarian tumors indicates that intervention strategies could be developed to specifically address subtypes of epithelial ovarian cancer

    Central-type primitive neuroectodermal tumor of the uterus: Case report of remission of stage IV disease using adjuvant cisplatin/etoposide/bevacizumab chemotherapy and review of the literature

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    • Bevacizumab was an effective agent in one case of advanced uterine PNET. • VEGF was expressed by the tumor, supporting a mechanism for effectiveness. • Cisplatin/etoposide/bevacizumab should be further studied in clinical trials. • Patient remains disease-free forty-eight months following intervention

    Differential methylation of genes in cluster-based analysis, p<0.05.

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    <p>1 = IPA network for Cell Cycle and Cell Morphology, 2 = IPA network for Inflammatory Response.</p>*<p>appears in supervised and unsupervised lists.</p

    Bulk methylation levels across genomic loci.

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    <p>Frequency of methylation at all loci for a given level of methylation (range 0 to 1). Each biological sample is represented as a single line; all non-metastatic samples were plotted. Respectively, panels from left to right contain all loci (N = 27,561), X chromosome only (N = 1038), or chromosome 10 only (N = 1044).</p

    Classification of 25 additional serous tumors.

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    <p>Methylation at 60 loci was used to evaluate an independent set of serous tumors. Each row represents an individual sample; each column corresponds to one of the previously identified differentially methylated sites. An empty box indicates methylation more similar to the control cluster (not necessarily unmethylated); a filled black box indicates methylation more similar to the cluster of ovarian serous tumors. Samples are ordered by the number of sites having methylation resembling the serous tumor group.</p

    Methylation status at top 500 most variable probes.

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    <p>Heatmap of methylation levels; blue = 0.0, black = 0.5, yellow = 1.0. At left, a representative sample of hierarchical clustering, and color blocks giving the consensus groups. Six columns on the right give sample characteristics: number; tumor (T) or normal (N); location in ovary (O), fallopian tube (F), or endometrium (E); histology of serous (S) or endometrioid (O); grade (1–3; where symbols used are ‘-’ for normals and ‘NA’ for information not available.) and at far right, dots for public TCGA data. Five samples at bottom are ovarian metastases from endometrial endometrioid tumors, excluded from the initial analysis and clustering.</p