Robust detection of translocations in lymphoma FFPE samples using targeted locus capture-based sequencing

Amin Allahyar, Mark Pieterse, Joost Swennenhuis, G. Tjitske Los- de Vries, Mehmet Yilmaz, Roos Leguit, Ruud W. J. Meijers, Robert Geize, Joost Vermaat, Arjen Cleven, Tom Wezel, Arjan Diepstra, Léon C. Kempen, Nathalie J. Hijmering, Phylicia Stathi, Milan Sharma, Adrien S. J. Melquiond, Paula J. P. Vree, Marjon J. A. M. Verstegen, Peter H. L. Krijger, Karima Hajo, Marieke Simonis, Agata Rakszewska, Max Min, Daphne Jong, Bauke Ylstra, Harma Feitsma, Erik Splinter () and Wouter Laat ()
Additional contact information
Amin Allahyar: Oncode Institute & Hubrecht Institute-KNAW and University Medical Center Utrecht
Mark Pieterse: Oncode Institute & Hubrecht Institute-KNAW and University Medical Center Utrecht
Joost Swennenhuis: Cergentis BV
G. Tjitske Los- de Vries: Amsterdam UMC-Vrije Universiteit Amsterdam, Department of Pathology and Cancer Center Amsterdam
Mehmet Yilmaz: Cergentis BV
Roos Leguit: University Medical Centre Utrecht, Department of Pathology
Ruud W. J. Meijers: University Medical Centre Utrecht, Department of Pathology
Robert Geize: Laboratorium Pathologie Oost-Nederland
Joost Vermaat: Leiden University Medical Centre, Department of Hematology
Arjen Cleven: Leiden University Medical Center, Department of Pathology
Tom Wezel: Leiden University Medical Center, Department of Pathology
Arjan Diepstra: University of Groningen, University Medical Centre Groningen, Department of Pathology & Medical Biology
Léon C. Kempen: University of Groningen, University Medical Centre Groningen, Department of Pathology & Medical Biology
Nathalie J. Hijmering: Amsterdam UMC-Vrije Universiteit Amsterdam, Department of Pathology and Cancer Center Amsterdam
Phylicia Stathi: Amsterdam UMC-Vrije Universiteit Amsterdam, Department of Pathology and Cancer Center Amsterdam
Milan Sharma: Oncode Institute & Hubrecht Institute-KNAW and University Medical Center Utrecht
Adrien S. J. Melquiond: Oncode Institute & Hubrecht Institute-KNAW and University Medical Center Utrecht
Paula J. P. Vree: Oncode Institute & Hubrecht Institute-KNAW and University Medical Center Utrecht
Marjon J. A. M. Verstegen: Oncode Institute & Hubrecht Institute-KNAW and University Medical Center Utrecht
Peter H. L. Krijger: Oncode Institute & Hubrecht Institute-KNAW and University Medical Center Utrecht
Karima Hajo: Cergentis BV
Marieke Simonis: Cergentis BV
Agata Rakszewska: Cergentis BV
Max Min: Cergentis BV
Daphne Jong: Amsterdam UMC-Vrije Universiteit Amsterdam, Department of Pathology and Cancer Center Amsterdam
Bauke Ylstra: Amsterdam UMC-Vrije Universiteit Amsterdam, Department of Pathology and Cancer Center Amsterdam
Harma Feitsma: Cergentis BV
Erik Splinter: Cergentis BV
Wouter Laat: Oncode Institute & Hubrecht Institute-KNAW and University Medical Center Utrecht

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract In routine diagnostic pathology, cancer biopsies are preserved by formalin-fixed, paraffin-embedding (FFPE) procedures for examination of (intra-) cellular morphology. Such procedures inadvertently induce DNA fragmentation, which compromises sequencing-based analyses of chromosomal rearrangements. Yet, rearrangements drive many types of hematolymphoid malignancies and solid tumors, and their manifestation is instructive for diagnosis, prognosis, and treatment. Here, we present FFPE-targeted locus capture (FFPE-TLC) for targeted sequencing of proximity-ligation products formed in FFPE tissue blocks, and PLIER, a computational framework that allows automated identification and characterization of rearrangements involving selected, clinically relevant, loci. FFPE-TLC, blindly applied to 149 lymphoma and control FFPE samples, identifies the known and previously uncharacterized rearrangement partners. It outperforms fluorescence in situ hybridization (FISH) in sensitivity and specificity, and shows clear advantages over standard capture-NGS methods, finding rearrangements involving repetitive sequences which they typically miss. FFPE-TLC is therefore a powerful clinical diagnostics tool for accurate targeted rearrangement detection in FFPE specimens.

Date: 2021
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DOI: 10.1038/s41467-021-23695-8

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