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Partner independent fusion gene detection by multiplexed CRISPR-Cas9 enrichment and long read nanopore sequencing

Author

Listed:
  • Christina Stangl

    (University Medical Center Utrecht and Utrecht University
    Plesmanlaan
    Oncode Institute)

  • Sam Blank

    (University Medical Center Utrecht and Utrecht University)

  • Ivo Renkens

    (University Medical Center Utrecht and Utrecht University)

  • Liset Westera

    (Princess Máxima Center for Pediatric Oncology
    Dutch Childhood Oncology Group (DCOG))

  • Tamara Verbeek

    (University Medical Center Utrecht and Utrecht University)

  • Jose Espejo Valle-Inclan

    (University Medical Center Utrecht and Utrecht University
    Oncode Institute)

  • Rocio Chamorro González

    (Charité-Universitätsmedizin Berlin
    Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin)

  • Anton G. Henssen

    (Charité-Universitätsmedizin Berlin
    Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin
    German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ)
    Berlin Institute of Health)

  • Markus J. Roosmalen

    (Oncode Institute
    Princess Máxima Center for Pediatric Oncology)

  • Ronald W. Stam

    (Princess Máxima Center for Pediatric Oncology)

  • Emile E. Voest

    (Plesmanlaan
    Oncode Institute)

  • Wigard P. Kloosterman

    (University Medical Center Utrecht and Utrecht University)

  • Gijs Haaften

    (University Medical Center Utrecht and Utrecht University)

  • Glen R. Monroe

    (University Medical Center Utrecht and Utrecht University)

Abstract

Fusion genes are hallmarks of various cancer types and important determinants for diagnosis, prognosis and treatment. Fusion gene partner choice and breakpoint-position promiscuity restricts diagnostic detection, even for known and recurrent configurations. Here, we develop FUDGE (FUsion Detection from Gene Enrichment) to accurately and impartially identify fusions. FUDGE couples target-selected and strand-specific CRISPR-Cas9 activity for fusion gene driver enrichment — without prior knowledge of fusion partner or breakpoint-location — to long read nanopore sequencing with the bioinformatics pipeline NanoFG. FUDGE has flexible target-loci choices and enables multiplexed enrichment for simultaneous analysis of several genes in multiple samples in one sequencing run. We observe on-average 665 fold breakpoint-site enrichment and identify nucleotide resolution fusion breakpoints within 2 days. The assay identifies cancer cell line and tumor sample fusions irrespective of partner gene or breakpoint-position. FUDGE is a rapid and versatile fusion detection assay for diagnostic pan-cancer fusion detection.

Suggested Citation

  • Christina Stangl & Sam Blank & Ivo Renkens & Liset Westera & Tamara Verbeek & Jose Espejo Valle-Inclan & Rocio Chamorro González & Anton G. Henssen & Markus J. Roosmalen & Ronald W. Stam & Emile E. Vo, 2020. "Partner independent fusion gene detection by multiplexed CRISPR-Cas9 enrichment and long read nanopore sequencing," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16641-7
    DOI: 10.1038/s41467-020-16641-7
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