Dataset Information

Integrative Transcriptome Analyses of the Human Fallopian Tube: Fimbria and Ampulla-Site of Origin of Serous Carcinoma of the Ovary.

ABSTRACT: Epithelial ovarian cancer represents a group of heterogeneous diseases with high grade serous cancer (HGSC) representing the most common histotype. Molecular profiles of precancerous lesions found in the fallopian tube have implicated this tissue as the presumptive site of origin of HGSC. Precancerous lesions are primarily found in the distal fallopian tube (fimbria), near the ovary relative to the proximal tissue (ampulla), nearer to the uterus. The proximity of the fimbria to the ovary and the link between ovulation, through follicular fluid release, and ovarian cancer risk led us to examine transcriptional responses of fallopian tube epithelia (FTE) at the different anatomical sites of the human fallopian tube. Gene expression profiles of matched FTE from the fimbria and from premenopausal women resulted in differentially expressed genes (DEGs): CYYR1, SALL1, FOXP2, TAAR1, AKR1C2/C3/C4, NMBR, ME1 and GSTA2. These genes are part of the antioxidant, stem and inflammation pathways. Comparisons between the luteal phase (post-ovulation) to the follicular phase (pre-ovulation) demonstrated greater differences in DEGs than a comparison between fimbria and fallopian tube anatomical differences alone. This data suggests that cyclical transcriptional changes experienced in pre-menopause are inherent physiological triggers that expose the FTE in the fimbria to cytotoxic stressors. These cyclical exposures induce transcriptional changes reflective of genotoxic and cytotoxic damage to the FTE in the fimbria which are closely related to transcriptional and genomic alterations observed in ovarian cancer.

SUBMITTER: Sowamber R

PROVIDER: S-EPMC7281286 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

Integrative Transcriptome Analyses of the Human Fallopian Tube: Fimbria and Ampulla-Site of Origin of Serous Carcinoma of the Ovary.

Sowamber Ramlogan R Nelson Omar O Dodds Leah L DeCastro Victoria V Paudel Iru I Milea Anca A Considine Michael M Cope Leslie L Pinto Andre A Schlumbrecht Matthew M Slomovitz Brian B Shaw Patricia A PA George Sophia H L SHL

Cancers 20200427 5

Epithelial ovarian cancer represents a group of heterogeneous diseases with high grade serous cancer (HGSC) representing the most common histotype. Molecular profiles of precancerous lesions found in the fallopian tube have implicated this tissue as the presumptive site of origin of HGSC. Precancerous lesions are primarily found in the distal fallopian tube (fimbria), near the ovary relative to the proximal tissue (ampulla), nearer to the uterus. The proximity of the fimbria to the ovary and the ...[more]

PMID: 32349388

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Project description:The cell and tissue of origin of high grade serous ovarian cancer (HGSC) is controversial. While the disease was traditionally assumed to arise from the ovarian surface epithelium (OSE), recent work supports an alternative model implicating the fallopian tube fimbriae epithelium (FTE). We used comparative DNA methylome analyses as a means to test these two competing models, hypothesizing that the HGSC methylome should more closely resemble its tissue of origin. Using two separate analysis methods, analysis within distinct genomic contexts, and validation studies using large-scale publically available HGSC methylome data, we consistently observed that the DNA methylome of HGSC more closely resembles FTE than OSE. These data support the FTE origin model, and suggest DNA methylome analysis as a useful approach to examine cell/tissue lineage origin in cancer. HGSC is the most common and lethal form of epithelial ovarian cancer (EOC). Two distinct tissues have been hypothesized as the tissue of origin of HGSC: OSE and FTE. We hypothesized that the DNA methylome of HGSC would more closely resemble the methylome of its tissue of origin. To test this, we profiled HGSC (n=10), OSE (n=7), and FTE (n=7) primary fresh-frozen tissues, and analyzed DNA methylome using Illumina 450K arrays (n=24) and Agilent Sure Select methyl-seq (n=7). We compared methylomes using statistical analyses of differentially methylated CpG sites (DMC) and differentially methylated regions (DMR), and methylation within a variety of different genomic contexts, including CpG island shores. We also analyzed methylation specifically at Homeobox (HOX) genes, due to their role in tissue specification. We used publically available HGSC methylome data (n=628) to provide additional comparison with FTE and OSE and potential validation. This analysis revealed that HGSC and FTE methylomes were significantly and consistently more highly conserved than were HGSC and OSE. Pearson correlations and hierarchal clustering of genes, promoters, CpG islands, CpG island shores, and HOX genes all revealed the increased relatedness of HGSC and FTE methylomes. In addition, two different large data sets of publically-available HGSC methylome data confirmed these relationships. In summary, our findings support the FTE origin model for HGSC, the most common and deadly EOC subtype. Due to its tissue-specificity and biochemical stability, interrogation of the DNA methylome appears to be a valuable approach to examine cell/tissue lineage in cancer.

Dataset Information

Integrative Transcriptome Analyses of the Human Fallopian Tube: Fimbria and Ampulla-Site of Origin of Serous Carcinoma of the Ovary.

Publications

Integrative Transcriptome Analyses of the Human Fallopian Tube: Fimbria and Ampulla-Site of Origin of Serous Carcinoma of the Ovary.

Similar Datasets

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