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

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. Voest, Wigard P. Kloosterman, Gijs Haaften and Glen R. Monroe ()
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Christina Stangl: University Medical Center Utrecht and Utrecht University
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
Tamara Verbeek: University Medical Center Utrecht and Utrecht University
Jose Espejo Valle-Inclan: University Medical Center Utrecht and Utrecht University
Rocio Chamorro González: Charité-Universitätsmedizin Berlin
Anton G. Henssen: Charité-Universitätsmedizin Berlin
Markus J. Roosmalen: Oncode Institute
Ronald W. Stam: Princess Máxima Center for Pediatric Oncology
Emile E. Voest: Plesmanlaan
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

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16641-7

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