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Heterotypic Three-dimensional In Vitro Modeling of Stromal-Epithelial Interactions During Ovarian Cancer Initiation and Progression
Published on: August 28, 2012
Involvement of DPP9 in gene fusions in serous ovarian carcinoma
Marianne Lislerud Smebye1,2, Antonio Agostini1,2, Bjarne Johannessen2,3
1Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Background:
A fusion gene is a hybrid gene consisting of parts from two previously independent genes. Chromosomal rearrangements leading to gene breakage are frequent in high-grade serous ovarian carcinomas and have been reported as a common mechanism for inactivating tumor suppressor genes. However, no fusion genes have been repeatedly reported to be recurrent driver events in ovarian carcinogenesis. We combined genomic and transcriptomic information to identify novel fusion gene candidates and aberrantly expressed genes in ovarian carcinomas.
Methods:
Examined were 19 previously karyotyped ovarian carcinomas (18 of the serous histotype and one undifferentiated). First, karyotypic aberrations were compared to fusion gene candidates identified by RNA sequencing (RNA-seq). In addition, we used exon-level gene expression microarrays as a screening tool to identify aberrantly expressed genes possibly involved in gene fusion events, and compared the findings to the RNA-seq data.
Results:
We found a DPP9-PPP6R3 fusion transcript in one tumor showing a matching genomic 11;19-translocation. Another tumor had a rearrangement of DPP9 with PLIN3. Both rearrangements were associated with diminished expression of the 3' end of DPP9 corresponding to the breakpoints identified by RNA-seq. For the exon-level expression analysis, candidate fusion partner genes were ranked according to deviating expression compared to the median of the sample set. The results were collated with data obtained from the RNA-seq analysis. Several fusion candidates were identified, among them TMEM123-MMP27, ZBTB46-WFDC13, and PLXNB1-PRKAR2A, all of which led to stronger expression of the 3' genes. In view of our previous findings of nonrandom rearrangements of chromosome 19 in this cancer type, particular emphasis was given to changes of this chromosome and a DDA1-FAM129C fusion event was identified.
Conclusions:
We have identified novel fusion gene candidates in high-grade serous ovarian carcinoma. DPP9 was involved in two different fusion transcripts that both resulted in deregulated expression of the 3' end of the transcript and thus possible loss of the active domains in the DPP9 protein. The identified rearrangements might play a role in tumorigenesis or tumor progression.
Insights
Researchers identified novel fusion genes in ovarian cancer, including DPP9 rearrangements that may impact tumor development. This study combined genomic and transcriptomic data to uncover these genetic alterations in high-grade serous ovarian carcinomas.
Area of Science:
- Genomics
- Transcriptomics
- Cancer Biology
Background:
- Fusion genes arise from two independent genes, often due to chromosomal rearrangements.
- Such rearrangements are common in high-grade serous ovarian carcinomas, frequently inactivating tumor suppressor genes.
- However, recurrent fusion genes as driver events in ovarian carcinogenesis remain largely unreported.
Purpose of the Study:
- To identify novel fusion gene candidates in ovarian carcinomas.
- To investigate aberrantly expressed genes potentially involved in gene fusion events.
- To correlate genomic and transcriptomic findings in ovarian cancer.
Main Methods:
- Analysis of 19 ovarian carcinomas (18 serous, 1 undifferentiated) with prior karyotyping.
- Comparison of karyotypic aberrations with fusion gene candidates identified via RNA sequencing (RNA-seq).
- Screening for aberrantly expressed genes using exon-level gene expression microarrays and comparison with RNA-seq data.
Main Results:
- A DPP9-PPP6R3 fusion transcript was found, linked to an 11;19-translocation and diminished DPP9 expression.
- Another tumor showed a DPP9-PLIN3 rearrangement, also associated with reduced DPP9 3' end expression.
- Additional fusion candidates identified include TMEM123-MMP27, ZBTB46-WFDC13, PLXNB1-PRKAR2A, and DDA1-FAM129C, some affecting chromosome 19.
Conclusions:
- Novel fusion gene candidates were identified in high-grade serous ovarian carcinoma.
- DPP9 was involved in two fusion transcripts, leading to deregulated expression and potential loss of protein domains.
- These identified rearrangements may contribute to ovarian tumorigenesis or progression.
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