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EBioMedicine. 2018 Nov;37:158-167. doi: 10.1016/j.ebiom.2018.10.059. Epub 2018 Oct 31.

The Landscape and Implications of Chimeric RNAs in Cervical Cancer.

Author information

1
The Key Laboratory of Cancer Invasion and Metastasis of the Ministry of Education of China, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
2
The Key Laboratory of Cancer Invasion and Metastasis of the Ministry of Education of China, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
3
Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
4
Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; National Institute of Plant Genome Research (NIPGR), New Delhi 110067, India.
5
The Key Laboratory of Cancer Invasion and Metastasis of the Ministry of Education of China, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: dma@tjh.tjmu.edu.cn.
6
Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China. Electronic address: hl9r@virginia.edu.

Abstract

BACKGROUND:

Gene fusions and fusion products have been proven to be ideal biomarkers and drug targets for cancer. Even though a comprehensive study of cervical cancer has been conducted as part of the Cancer Genome Atlas (TCGA) project, few recurrent gene fusions have been found, and none above 3% of frequency.

METHODS:

We believe that chimeric fusion RNAs generated by intergenic splicing represent a new repertoire of biomarkers and/or therapeutic targets. However, they would be missed when only genome sequences and fusions at DNA level are considered. We performed extensive data mining for chimeric RNAs using both our and TCGA cervical cancer RNA-Seq datasets. Multiple criteria were applied. We analyzed the landscape of chimeric RNAs at various levels, and from different angles.

FINDINGS:

The chimeric RNA landscape changed as different filters were applied. 15 highly frequent (>10%) chimeric RNAs were identified. LHX6-NDUFA8 was detected exclusively in cervical cancer tissues and Pap smears, but not in normal controls. Mechanistically, it is not due to interstitial deletion, but a product of cis-splicing between adjacent genes. Silencing of another recurrent chimera, SLC2A11-MIF, resulted in cell cycle arrest and reduced cellular proliferation. This effect is unique to the chimera, and not shared by the two parental genes.

INTERPRETATION:

Highly frequent chimeric RNAs are present in cervical cancers. They can be formed by intergenic splicing. Some have clear implications as potential biomarkers, or for shedding new light on the biology of the disease. FUND: Stand Up To Cancer and the National Science Foundation of China.

KEYWORDS:

Bioinformatics; Cervical cancer; Chimeric RNA; Gene fusion; RNA-Seq

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