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| Status |
Public on May 10, 2016 |
| Title |
DNA methylome analyses implicate fallopian tube as the tissue of origin for high grade serous ovarian cancer [array] |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by genome tiling array
|
| Summary |
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.
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| Overall design |
Obtained fresh-frozen high grade serous cancer (HGSC) samples (n=10) from patients undergoing surgical resection at Roswell Park Cancer Institute (RPCI) and fresh-frozen patient matched normal ovarian surface epithelial (OSE) cells (n=5) and fallopian tube epithelial (FTE) cells (n=5) from patients without malignancy. Used mechanical scraping and processing of the epithelial layer of resected ovaries and fimbriae fallopian tubes immediately after removal in the operating theater. All samples were collected using IRB-approved protocols at RPCI. Isolated genomic DNA using the Puregene Tissue Kit (Qiagen), which includes RNAse treatment. To eliminate potentially confounding effects due to methylation phenotype, we selected HGSC samples showing similar global methylation as FTE and OSE, as determined by LINE-1 pyrosequencing. Genomic DNA (1000ng) was bisulfite converted using EZ DNA Methylation-Direct kit (Zimo Research) following the manufacturer's protocol. Samples were hybridized to Infinium Human Methylation 450K BeadChips (Illumina) according to the manufacturer's protocol. Arrays were scanned on Iscan (Illumina).
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| Contributor(s) |
Karpf AR |
| Citation(s) |
27259716 |
| |
| Submission date |
May 09, 2016 |
| Last update date |
Mar 22, 2019 |
| Contact name |
Adam R. Karpf |
| E-mail(s) |
adam.karpf@unmc.edu
|
| Phone |
402-559-6115
|
| Organization name |
University of Nebraska Medical Center
|
| Department |
Eppley Institute for Research in Cancer
|
| Street address |
985950 Nebraska Medical Center
|
| City |
Omaha |
| State/province |
Nebraska |
| ZIP/Postal code |
68198-5950 |
| Country |
USA |
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| Platforms (1) |
| GPL13534 |
Illumina HumanMethylation450 BeadChip (HumanMethylation450_15017482) |
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| Samples (20)
|
| GSM2146822 |
fallopian tube epithelial cells (FTE11) |
| GSM2146823 |
fallopian tube epithelial cells (FTE18) |
| GSM2146824 |
fallopian tube epithelial cells (FTE19) |
| GSM2146825 |
fallopian tube epithelial cells (FTE21) |
| GSM2146826 |
fallopian tube epithelial cells (FTE22) |
| GSM2146827 |
high grade serous ovarian cancer (EOC11) |
| GSM2146828 |
high grade serous ovarian cancer (EOC12) |
| GSM2146829 |
high grade serous ovarian cancer (EOC150) |
| GSM2146830 |
high grade serous ovarian cancer (EOC5) |
| GSM2146831 |
high grade serous ovarian cancer (EOC54) |
| GSM2146832 |
high grade serous ovarian cancer (EOC59) |
| GSM2146833 |
high grade serous ovarian cancer (EOC66) |
| GSM2146834 |
high grade serous ovarian cancer (EOC82) |
| GSM2146835 |
high grade serous ovarian cancer (EOC83) |
| GSM2146836 |
high grade serous ovarian cancer (EOC99) |
| GSM2146837 |
normal ovarian surface epithelial cells (OSE11) |
| GSM2146838 |
normal ovarian surface epithelial cells (OSE18) |
| GSM2146839 |
normal ovarian surface epithelial cells (OSE19) |
| GSM2146840 |
normal ovarian surface epithelial cells (OSE21) |
| GSM2146841 |
normal ovarian surface epithelial cells (OSE22) |
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| This SubSeries is part of SuperSeries: |
| GSE81228 |
DNA methylome analyses implicate fallopian tube as the tissue of origin for high grade serous ovarian cancer |
|
| Relations |
| BioProject |
PRJNA320993 |
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