Novel kinase fusion transcripts found in endometrial cancer.

Ryo Tamura,Kosuke Yoshihara,Kaoru Yamawaki,Takayuki Enomoto,Roel G W Verhaak,Shujiro Okuda,Kazuaki Suda,Ituro Inoue,Tatsuya Ishiguro,Sosuke Adachi

doi:10.1038/srep18657

Ryo Tamura, Kosuke Yoshihara + Show 8 more

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https://doi.org/10.1038/srep18657

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Recent advances in RNA-sequencing technology have enabled the discovery of gene fusion transcripts in the transcriptome of cancer cells. However, it remains difficult to differentiate the therapeutically targetable fusions from passenger events. We have analyzed RNA-sequencing data and DNA copy number data from 25 endometrial cancer cell lines to identify potential therapeutically targetable fusion transcripts, and have identified 124 high-confidence fusion transcripts, of which 69% are associated with gene amplifications. As targetable fusion candidates, we focused on three in-frame kinase fusion transcripts that retain a kinase domain (CPQ-PRKDC, CAPZA2-MET, and VGLL4-PRKG1). We detected only CPQ-PRKDC fusion transcript in three of 122 primary endometrial cancer tissues. Cell proliferation of the fusion-positive cell line was inhibited by knocking down the expression of wild-type PRKDC but not by blocking the CPQ-PRKDC fusion transcript expression. Quantitative real-time RT-PCR demonstrated that the expression of the CPQ-PRKDC fusion transcript was significantly lower than that of wild-type PRKDC, corresponding to a low transcript allele fraction of this fusion, based on RNA-sequencing read counts. In endometrial cancers, the CPQ-PRKDC fusion transcript may be a passenger aberration related to gene amplification. Our findings suggest that transcript allele fraction is a useful predictor to find bona-fide therapeutic-targetable fusion transcripts.

Highlights

We have combined RNA-sequencing data from 25 endometrial cancer cell lines with array data of matched small nucleotide polymorphisms (SNPs) obtained from the Cancer Cell Line Encyclopedia (CCLE, http://www. broadinstitute.org/ccle) to define the landscape of gene-fusion transcripts in endometrial cancer cells, with the intention of discovering new potential therapeutic molecular targets for endometrial cancer
After removing the overlapping fusion pairs, with 158 kinds of fusion transcripts discovered in 364 normal tissues samples[11], we identified 124 cancer-specific fusion transcripts from the 25 endometrial cancer cell lines (Supplementary Table S2)
To compare the transcript allele fraction (TAF) of the kinase in-frame fusion transcripts between endometrial cancer cell lines and TCGA clinical samples, we used 7,887 fusion transcripts detected in 4,366 TCGA samples across 13 tumor types[11]

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Introduction

We have combined RNA-sequencing data from 25 endometrial cancer cell lines with array data of matched small nucleotide polymorphisms (SNPs) obtained from the Cancer Cell Line Encyclopedia (CCLE, http://www. broadinstitute.org/ccle) to define the landscape of gene-fusion transcripts in endometrial cancer cells, with the intention of discovering new potential therapeutic molecular targets for endometrial cancer. After removing the overlapping fusion pairs, with 158 kinds of fusion transcripts discovered in 364 normal tissues samples[11], we identified 124 cancer-specific fusion transcripts from the 25 endometrial cancer cell lines (Supplementary Table S2). As of May 1, 2015, only 26 of 124 cancer-specific fusion transcripts were previously reported in the TCGA Fusion Gene Data Portal (http://www.tumorfusions.org) (Fig. 1b and Supplementary Table S2).

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