Common Fusion Transcripts Identified in Colorectal Cancer Cell Lines by High-Throughput RNA Sequencing

Nome, Torfinn; Thomassen, Gard; Bruun, Jarle; Ahlquist, Terje Cruickshank; Bakken, Anne Cathrine; Hoff, Andreas; Rognum, Torleiv O.; Nesbakken, Arild; Lorenz, Susanne; Sun, Jinchang; Barros-Silva, João D.; Lind, Guro Elisabeth; Myklebost, Ola; Teixeira, Manuel R.; Meza‐Zepeda, Leonardo A.; Skotheim, Rolf Inge

doi:10.1593/tlo.13457

Cited by 28 publications

(29 citation statements)

References 44 publications

(49 reference statements)

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“…Exon-level expression profiles for all candidate genes can be found in supplementary Figure S1 . One candidate gene ( S100A2 ) has previously been nominated from RNA sequencing data as a downstream partner of three fusion transcripts in the CRC cell line RKO, with ZNF833 , RP1–28O10.1 , and AMPD3 as 5′ fusion partners [ 25 ]. An overview of the pipeline used to identify and characterize novel RNA variants in CRC is provided in Figure 1 .…”

Section: Resultsmentioning

confidence: 99%

Novel RNA variants in colorectal cancers

et al. 2015

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With an annual estimated incidence of 1.4 million, and a five-year survival rate of 60%, colorectal cancer (CRC) is a major clinical burden. To identify novel RNA variants in CRC, we analyzed exon-level microarray expression data from a cohort of 202 CRCs. We nominated 25 genes with increased expression of their 3′ parts in at least one cancer sample each. To efficiently investigate underlying transcript structures, we developed an approach using rapid amplification of cDNA ends followed by high throughput sequencing (RACE-seq). RACE products from the targeted genes in 23 CRC samples were pooled together and sequenced. We identified VWA2-TCF7L2, DHX35-BPIFA2 and CASZ1-MASP2 as private fusion events, and novel transcript structures for 17 of the 23 other candidate genes. The high-throughput approach facilitated identification of CRC specific RNA variants. These include a recurrent read-through fusion transcript between KLK8 and KLK7, and a splice variant of S100A2. Both of these were overrepresented in CRC tissue and cell lines from external RNA-seq datasets.

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Section: Resultsmentioning

confidence: 99%

Novel RNA variants in colorectal cancers

et al. 2015

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“…13). Whole-exome paired-end sequencing was carried out using the Illumina TruSeq DNA Sample Prep Kit, followed by the Illumina TruSeq Exome Enrichment Kit (Illumina Inc.), and sequencing was subsequently performed on an Illumina Genome Analyzer IIx…”

Section: Massive Parallel Sequencingmentioning

confidence: 99%

Regulator of Chromosome Condensation 2 Identifies High-Risk Patients within Both Major Phenotypes of Colorectal Cancer

Bruun

Kolberg

Ahlquist

et al. 2015

Clinical Cancer Research

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Purpose: Colorectal cancer has high incidence and mortality worldwide. Patients with microsatellite instable (MSI) tumors have significantly better prognosis than patients with microsatellite stable (MSS) tumors. Considerable variation in disease outcome remains a challenge within each subgroup, and our purpose was to identify biomarkers that improve prediction of colorectal cancer prognosis.Experimental Design: Mutation analyses of 42 MSI target genes were performed in two independent MSI tumor series (n ¼ 209). Markers that were significantly associated with prognosis in the test series were assessed in the validation series, followed by functional and genetic explorations. The clinical potential was further investigated by immunohistochemistry in a population-based colorectal cancer series (n ¼ 903).Results: We identified the cell-cycle gene regulator of chromosome condensation 2 (RCC2) as a cancer biomarker. We found a mutation in the 5 0 UTR region of RCC2 that in univariate and multivariate analyses was significantly associated with improved outcome in the MSI group. This mutation caused reduction of protein expression in dual luciferase gene reporter assays. siRNA knockdown in MSI colon cancer cells (HCT15) caused reduced cell proliferation, cell-cycle arrest, and increased apoptosis. Massive parallel sequencing revealed few RCC2 mutations in MSS tumors. However, weak RCC2 protein expression was significantly associated with poor prognosis, independent of clinical highrisk parameters, and stratifies clinically important patient subgroups with MSS tumors, including elderly patients (>75 years), stage II patients, and those with rectal cancer.Conclusions: Impaired RCC2 affects functional and clinical endpoints of colorectal cancer. High-risk patients with either MSI or MSS tumors can be identified with cost-effective routine RCC2 assays.

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“…PDE8A in particular was prominently expressed, at the mRNA level, in all of the established breast cancer cell lines and patients' tissues examined, although as a result of compartmentalization, even PDEs with lower mRNA expressions can have profound effects on cell function and pathophysiology. It is of note that expression of PDE8A in the form of an AKAP13-PDE8A fusion transcript is also highly recurrent in colorectal cancer [46]. We demonstrate in this study that breast cancer cell migration is significantly inhibited by activation of cAMP signaling through either application of cell permeable cAMP analogs or by treatment with PDE inhibitors.…”

Section: Discussionmentioning

confidence: 55%

Inhibition of breast cancer cell migration by activation of cAMP signaling

Dong

Claffey

Brocke

et al. 2015

Breast Cancer Res Treat

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Almost all deaths from breast cancer arise from metastasis of the transformed cells to other sites in the body. Hence, uncovering a means of inhibiting breast cancer cell migration would provide a significant advance in the treatment of this disease. Stimulation of the cAMP signaling pathway has been shown to inhibit migration and motility of a number of cell types. A very effective way of selectively stimulating cAMP signaling is through inhibition of cyclic nucleotide phosphodiesterases (PDEs). Therefore, we examined full expression profiles of all known PDE genes at the mRNA and protein levels in four human breast cancer cell lines and eight patients' breast cancer tissues. By these analyses, expression of almost all PDE genes was seen in both cell lines and tissues. In the cell lines, appreciable expression was seen for PDEs 1C, 2A, 3B, 4A, 4B, 4D, 5A, 6B, 6C, 7A, 7B, 8A, 9A, 10A, and 11A. In patients' tissues, appreciable expression was seen for PDEs 1A, 3B, 4A, 4B, 4C, 4D, 5A, 6B, 6C, 7A, 7B, 8A, 8B, and 9A. PDE8A mRNA in particular is prominently expressed in all cell lines and patients' tissue samples examined. We show here that stimulation of cAMP signaling with cAMP analogs, forskolin, and PDE inhibitors, including selective inhibitors of PDE3, PDE4, PDE7, and PDE8, inhibit aggressive triple negative MDA-MB-231 breast cancer cell migration. Under the same conditions, these agents had little effect on breast cancer cell proliferation. This study demonstrates that PDE inhibitors inhibit breast cancer cell migration, and thus may be valuable therapeutic targets for inhibition of breast cancer metastasis. Since PDE8A is expressed in all breast cancer samples, and since dipyridamole, which inhibits PDE8, and PF-04957325, a selective PDE8 inhibitor, both inhibit migration, it suggests that PDE8A may be a valuable novel target for treatment of this disease.

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Common Fusion Transcripts Identified in Colorectal Cancer Cell Lines by High-Throughput RNA Sequencing

Cited by 28 publications

References 44 publications

Novel RNA variants in colorectal cancers

Novel RNA variants in colorectal cancers

Regulator of Chromosome Condensation 2 Identifies High-Risk Patients within Both Major Phenotypes of Colorectal Cancer

Inhibition of breast cancer cell migration by activation of cAMP signaling

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