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Patient-derived Orthotopic Xenograft Models for Human Urothelial Cell Carcinoma and Colorectal Cancer Tumor Growth and Spontaneous Metastasis
Published on: May 12, 2019
The landscape of chimeric RNAs in bladder urothelial carcinoma
Dingjun Zhu1, Sandeep Singh2, Xu Chen3
1Department of Urology, Sun Yat-sen Memorial Hospital, 107th Yanjiangxi Road, Yuexiu District, 510120, Guangzhou, Guangdong Province, China; Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22908, United States.
Background:
Gene fusions and products have been identified as oncogenic drivers in many cancers, making them attractive diagnostic markers and therapeutic targets. However, the landscape of fusion transcripts in bladder cancer has not been fully characterized.
Methods:
To identify fusion transcripts with potential therapeutic or diagnostic values, TCGA bladder urothelial carcinoma RNA-sequencing dataset was used. In order to avoid false positives, we applied multiple criteria including filtering out fusions detected in normal samples from GTEx dataset. We validated a subset of candidate fusions with a collection of bladder cancer and adjacent normal samples.
Result:
We identified 19,547 high confidence fusion genes from 414 bladder cancer samples. After filtering off M/M fusions, fusions in GTEx normal samples, and occurrence frequency <5, we obtained a list of 271 gene fusions, 13 of which were novel and specific to cancer samples. Six of those fusions were validated using cell lines and clinical samples. We discovered that two chimeric RNAs, BCL2L2-PABPN1 and CHFR-GOLGA3, were detected to be expressed significantly higher in bladder cancer samples compared to adjacent normal samples. Impressively, the wild-type of the parental genes were not differentially expressed. Mechanistically, we demonstrated that these two fusions are generated by cis-splicing between adjacent genes. These two fusions were detected mainly in the fraction of cell nucleus, suggesting a potential long noncoding RNA role.
Conclusion:
Our findings provide a panoramic view of the landscape of chimeric RNAs in bladder cancer. Some frequent chimeric RNAs are generated by intergenic splicing, and represent a new repertoire for potential biomarkers.
Insights
Researchers identified novel gene fusions in bladder cancer, revealing potential new biomarkers. Two specific chimeric RNAs, BCL2L2-PABPN1 and CHFR-GOLGA3, show higher expression in tumors, suggesting diagnostic and therapeutic value.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Gene fusions are recognized as key drivers of oncogenesis in various cancers.
- These fusion transcripts present opportunities for cancer diagnostics and targeted therapies.
- The comprehensive landscape of fusion transcripts in bladder cancer remains largely uncharacterized.
Purpose of the Study:
- To identify and characterize fusion transcripts within bladder cancer.
- To discover novel fusion transcripts with potential diagnostic or therapeutic significance.
- To investigate the mechanistic origins and cellular localization of identified fusions.
Main Methods:
- Utilized RNA-sequencing data from The Cancer Genome Atlas (TCGA) bladder urothelial carcinoma cohort.
- Applied stringent filtering criteria, including exclusion of fusions from normal GTEx samples, to minimize false positives.
- Validated candidate fusion transcripts in clinical bladder cancer and adjacent normal tissue samples.
Main Results:
- Identified 19,547 high-confidence fusion genes across 414 bladder cancer samples.
- Filtered down to 271 gene fusions, including 13 novel fusions specific to cancer.
- Validated six fusions, with BCL2L2-PABPN1 and CHFR-GOLGA3 showing significantly higher expression in bladder tumors, originating from cis-splicing and localized to the nucleus.
Conclusions:
- Provides a comprehensive overview of the chimeric RNA landscape in bladder cancer.
- Highlights intergenic splicing as a mechanism generating frequent chimeric RNAs.
- Suggests these novel chimeric RNAs represent a new class of potential biomarkers for bladder cancer.
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