Identification of fusion genes in breast cancer by paired-end RNA-sequencing

Henrik Edgren, Astrid Murumaegi, Sara Kangaspeska, Daniel Nicorici, Vesa Hongisto, Kristine Kleivi, Inga H. Rye, Sandra Nyberg, Maija Wolf, Anne-Lise Børresen-Dale, Olli Kallioniemi (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

187 Citations (Scopus)

Abstract

Background
Until recently, chromosomal translocations and fusion genes have been an underappreciated class of mutations in solid tumors. Next-generation sequencing technologies provide an opportunity for systematic characterization of cancer cell transcriptomes, including the discovery of expressed fusion genes resulting from underlying genomic rearrangements.

Results
We applied paired-end RNA-seq to identify 24 novel and 3 previously known fusion genes in breast cancer cells. Supported by an improved bioinformatic approach, we had a 95% success rate of validating gene fusions initially detected by RNA-seq. Fusion partner genes were found to contribute promoters (5' UTR), coding sequences and 3' UTRs. Most fusion genes were associated with copy number transitions and were particularly common in high-level DNA amplifications. This suggests that fusion events may contribute to the selective advantage provided by DNA amplifications and deletions. Some of the fusion partner genes, such as GSDMB in the TATDN1-GSDMB fusion and IKZF3 in the VAPB-IKZF3 fusion, were only detected as a fusion transcript, indicating activation of a dormant gene by the fusion event. A number of fusion gene partners have either been previously observed in oncogenic gene fusions, mostly in leukemias, or otherwise reported to be oncogenic. RNA interference-mediated knock-down of the VAPB-IKZF3 fusion gene indicated that it may be necessary for cancer cell growth and survival.

Conclusions
In summary, using RNA-sequencing and improved bioinformatic stratification, we have discovered a number of novel fusion genes in breast cancer, and identified VAPB-IKZF3 as a potential fusion gene with importance for the growth and survival of breast cancer cells.
Original languageEnglish
Article numberR6
JournalGenome Biology
Volume12
Issue number1
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

Fingerprint

RNA Sequence Analysis
gene fusion
Gene Fusion
breast neoplasms
RNA
cancer
sequence analysis
Breast Neoplasms
gene
bioinformatics
Computational Biology
amplification
gene activation
5' untranslated regions
DNA
3' untranslated regions
RNA interference
leukemia
Neoplasms
transcriptome

Keywords

  • breast cancer
  • cancer

Cite this

Edgren, H., Murumaegi, A., Kangaspeska, S., Nicorici, D., Hongisto, V., Kleivi, K., ... Kallioniemi, O. (2011). Identification of fusion genes in breast cancer by paired-end RNA-sequencing. Genome Biology, 12(1), [R6]. https://doi.org/10.1186/gb-2011-12-1-r6
Edgren, Henrik ; Murumaegi, Astrid ; Kangaspeska, Sara ; Nicorici, Daniel ; Hongisto, Vesa ; Kleivi, Kristine ; Rye, Inga H. ; Nyberg, Sandra ; Wolf, Maija ; Børresen-Dale, Anne-Lise ; Kallioniemi, Olli. / Identification of fusion genes in breast cancer by paired-end RNA-sequencing. In: Genome Biology. 2011 ; Vol. 12, No. 1.
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title = "Identification of fusion genes in breast cancer by paired-end RNA-sequencing",
abstract = "BackgroundUntil recently, chromosomal translocations and fusion genes have been an underappreciated class of mutations in solid tumors. Next-generation sequencing technologies provide an opportunity for systematic characterization of cancer cell transcriptomes, including the discovery of expressed fusion genes resulting from underlying genomic rearrangements.ResultsWe applied paired-end RNA-seq to identify 24 novel and 3 previously known fusion genes in breast cancer cells. Supported by an improved bioinformatic approach, we had a 95{\%} success rate of validating gene fusions initially detected by RNA-seq. Fusion partner genes were found to contribute promoters (5' UTR), coding sequences and 3' UTRs. Most fusion genes were associated with copy number transitions and were particularly common in high-level DNA amplifications. This suggests that fusion events may contribute to the selective advantage provided by DNA amplifications and deletions. Some of the fusion partner genes, such as GSDMB in the TATDN1-GSDMB fusion and IKZF3 in the VAPB-IKZF3 fusion, were only detected as a fusion transcript, indicating activation of a dormant gene by the fusion event. A number of fusion gene partners have either been previously observed in oncogenic gene fusions, mostly in leukemias, or otherwise reported to be oncogenic. RNA interference-mediated knock-down of the VAPB-IKZF3 fusion gene indicated that it may be necessary for cancer cell growth and survival.ConclusionsIn summary, using RNA-sequencing and improved bioinformatic stratification, we have discovered a number of novel fusion genes in breast cancer, and identified VAPB-IKZF3 as a potential fusion gene with importance for the growth and survival of breast cancer cells.",
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Edgren, H, Murumaegi, A, Kangaspeska, S, Nicorici, D, Hongisto, V, Kleivi, K, Rye, IH, Nyberg, S, Wolf, M, Børresen-Dale, A-L & Kallioniemi, O 2011, 'Identification of fusion genes in breast cancer by paired-end RNA-sequencing', Genome Biology, vol. 12, no. 1, R6. https://doi.org/10.1186/gb-2011-12-1-r6

Identification of fusion genes in breast cancer by paired-end RNA-sequencing. / Edgren, Henrik; Murumaegi, Astrid; Kangaspeska, Sara; Nicorici, Daniel; Hongisto, Vesa; Kleivi, Kristine; Rye, Inga H.; Nyberg, Sandra; Wolf, Maija; Børresen-Dale, Anne-Lise; Kallioniemi, Olli (Corresponding Author).

In: Genome Biology, Vol. 12, No. 1, R6, 2011.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Identification of fusion genes in breast cancer by paired-end RNA-sequencing

AU - Edgren, Henrik

AU - Murumaegi, Astrid

AU - Kangaspeska, Sara

AU - Nicorici, Daniel

AU - Hongisto, Vesa

AU - Kleivi, Kristine

AU - Rye, Inga H.

AU - Nyberg, Sandra

AU - Wolf, Maija

AU - Børresen-Dale, Anne-Lise

AU - Kallioniemi, Olli

PY - 2011

Y1 - 2011

N2 - BackgroundUntil recently, chromosomal translocations and fusion genes have been an underappreciated class of mutations in solid tumors. Next-generation sequencing technologies provide an opportunity for systematic characterization of cancer cell transcriptomes, including the discovery of expressed fusion genes resulting from underlying genomic rearrangements.ResultsWe applied paired-end RNA-seq to identify 24 novel and 3 previously known fusion genes in breast cancer cells. Supported by an improved bioinformatic approach, we had a 95% success rate of validating gene fusions initially detected by RNA-seq. Fusion partner genes were found to contribute promoters (5' UTR), coding sequences and 3' UTRs. Most fusion genes were associated with copy number transitions and were particularly common in high-level DNA amplifications. This suggests that fusion events may contribute to the selective advantage provided by DNA amplifications and deletions. Some of the fusion partner genes, such as GSDMB in the TATDN1-GSDMB fusion and IKZF3 in the VAPB-IKZF3 fusion, were only detected as a fusion transcript, indicating activation of a dormant gene by the fusion event. A number of fusion gene partners have either been previously observed in oncogenic gene fusions, mostly in leukemias, or otherwise reported to be oncogenic. RNA interference-mediated knock-down of the VAPB-IKZF3 fusion gene indicated that it may be necessary for cancer cell growth and survival.ConclusionsIn summary, using RNA-sequencing and improved bioinformatic stratification, we have discovered a number of novel fusion genes in breast cancer, and identified VAPB-IKZF3 as a potential fusion gene with importance for the growth and survival of breast cancer cells.

AB - BackgroundUntil recently, chromosomal translocations and fusion genes have been an underappreciated class of mutations in solid tumors. Next-generation sequencing technologies provide an opportunity for systematic characterization of cancer cell transcriptomes, including the discovery of expressed fusion genes resulting from underlying genomic rearrangements.ResultsWe applied paired-end RNA-seq to identify 24 novel and 3 previously known fusion genes in breast cancer cells. Supported by an improved bioinformatic approach, we had a 95% success rate of validating gene fusions initially detected by RNA-seq. Fusion partner genes were found to contribute promoters (5' UTR), coding sequences and 3' UTRs. Most fusion genes were associated with copy number transitions and were particularly common in high-level DNA amplifications. This suggests that fusion events may contribute to the selective advantage provided by DNA amplifications and deletions. Some of the fusion partner genes, such as GSDMB in the TATDN1-GSDMB fusion and IKZF3 in the VAPB-IKZF3 fusion, were only detected as a fusion transcript, indicating activation of a dormant gene by the fusion event. A number of fusion gene partners have either been previously observed in oncogenic gene fusions, mostly in leukemias, or otherwise reported to be oncogenic. RNA interference-mediated knock-down of the VAPB-IKZF3 fusion gene indicated that it may be necessary for cancer cell growth and survival.ConclusionsIn summary, using RNA-sequencing and improved bioinformatic stratification, we have discovered a number of novel fusion genes in breast cancer, and identified VAPB-IKZF3 as a potential fusion gene with importance for the growth and survival of breast cancer cells.

KW - breast cancer

KW - cancer

U2 - 10.1186/gb-2011-12-1-r6

DO - 10.1186/gb-2011-12-1-r6

M3 - Article

VL - 12

JO - Genome Biology

JF - Genome Biology

SN - 1474-7596

IS - 1

M1 - R6

ER -

Edgren H, Murumaegi A, Kangaspeska S, Nicorici D, Hongisto V, Kleivi K et al. Identification of fusion genes in breast cancer by paired-end RNA-sequencing. Genome Biology. 2011;12(1). R6. https://doi.org/10.1186/gb-2011-12-1-r6