Use of Whole-Genome Sequencing to Diagnose a Cryptic Fusion Oncogene

John S WELCH; Michael H TOMASSON; Peter WESTERVELT; Joelle VEIZER; Heather SCHMIDT; Tammi L VICKERY; Sharon HEATH; Mark A WATSON; Daniel C LINK; Timothy A GRAUBERT; John F DIPERSIO; Elaine R MARDIS; Li Ding; Timothy J LEY; Richard K WILSON; David E LARSON; Jeffery M KLCO; Shashikant KULKARNI; John WALLIS; KEN CHEN; Jacqueline E PAYTON; Robert S FULTON

doi:10.1001/jama.2011.497

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Use of Whole-Genome Sequencing to Diagnose a Cryptic Fusion Oncogene

Journal article

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Use of Whole-Genome Sequencing to Diagnose a Cryptic Fusion Oncogene

John S WELCH, Michael H TOMASSON, Peter WESTERVELT, Joelle VEIZER, Heather SCHMIDT, Tammi L VICKERY, Sharon HEATH, Mark A WATSON, Daniel C LINK, Timothy A GRAUBERT, …

JAMA : the journal of the American Medical Association, Vol.305(15), pp.1577-1584

2011

DOI: 10.1001/jama.2011.497

PMCID: PMC3156695

PMID: 21505136

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Abstract

Context Whole-genome sequencing is becoming increasingly available for research purposes, but it has not yet been routinely used for clinical diagnosis. Objective To determine whether whole-genome sequencing can identify cryptic, actionable mutations in a clinically relevant time frame. Design, Setting, and Patient We were referred a difficult diagnostic case of acute promyelocytic leukemia with no pathogenic X-RARA fusion identified by routine metaphase cytogenetics or interphase fluorescence in situ hybridization (FISH). The case patient was enrolled in an institutional review board–approved protocol, with consent specifically tailored to the implications of whole-genome sequencing. The protocol uses a “movable firewall” that maintains patient anonymity within the entire research team but allows the research team to communicate medically relevant information to the treating physician. Main Outcome Measures Clinical relevance of whole-genome sequencing and time to communicate validated results to the treating physician. Results Massively parallel paired-end sequencing allowed identification of a cytogenetically cryptic event: a 77-kilobase segment from chromosome 15 was inserted en bloc into the second intron of the RARA gene on chromosome 17, resulting in a classic bcr3 PML-RARA fusion gene. Reverse transcription polymerase chain reaction sequencing subsequently validated the expression of the fusion transcript. Novel FISH probes identified 2 additional cases of t(15;17)–negative acute promyelocytic leukemia that had cytogenetically invisible insertions. Whole-genome sequencing and validation were completed in 7 weeks and changed the treatment plan for the patient. Conclusion Whole-genome sequencing can identify cytogenetically invisible oncogenes in a clinically relevant time frame.

Biological and medical sciences

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Medical sciences

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Title: Subtitle: Use of Whole-Genome Sequencing to Diagnose a Cryptic Fusion Oncogene
Creators: John S WELCH - Departments of Medicine, Washington University, St Louis, Missouri, United States
Michael H TOMASSON - Departments of Medicine, Washington University, St Louis, Missouri, United States
Peter WESTERVELT - Departments of Medicine, Washington University, St Louis, Missouri, United States
Joelle VEIZER - Department of Genome Institute, Washington University, St Louis, Missouri, United States
Heather SCHMIDT - Department of Genome Institute, Washington University, St Louis, Missouri, United States
Tammi L VICKERY - Department of Genome Institute, Washington University, St Louis, Missouri, United States
Sharon HEATH - Departments of Medicine, Washington University, St Louis, Missouri, United States
Mark A WATSON - Department of Pathology and Immunology, Washington University, St Louis, Missouri, United States
Daniel C LINK - Departments of Medicine, Washington University, St Louis, Missouri, United States
Timothy A GRAUBERT - Departments of Medicine, Washington University, St Louis, Missouri, United States
John F DIPERSIO - Departments of Medicine, Washington University, St Louis, Missouri, United States
Elaine R MARDIS - Department of Genetics, Washington University, St Louis, Missouri, United States
Li Ding - Department of Genome Institute, Washington University, St Louis, Missouri, United States
Timothy J LEY - Department of Genetics, Washington University, St Louis, Missouri, United States
Richard K WILSON - Department of Genetics, Washington University, St Louis, Missouri, United States
David E LARSON - Department of Genome Institute, Washington University, St Louis, Missouri, United States
Jeffery M KLCO - Department of Pathology and Immunology, Washington University, St Louis, Missouri, United States
Shashikant KULKARNI - Department of Pathology and Immunology, Washington University, St Louis, Missouri, United States
John WALLIS - Department of Genome Institute, Washington University, St Louis, Missouri, United States
KEN CHEN - Department of Genome Institute, Washington University, St Louis, Missouri, United States
Jacqueline E PAYTON - Department of Pathology and Immunology, Washington University, St Louis, Missouri, United States
Robert S FULTON - Department of Genome Institute, Washington University, St Louis, Missouri, United States
Resource Type: Journal article
Publication Details: JAMA : the journal of the American Medical Association, Vol.305(15), pp.1577-1584
DOI: 10.1001/jama.2011.497
PMID: 21505136
PMCID: PMC3156695
NLM abbreviation: JAMA
ISSN: 0098-7484
eISSN: 1538-3598
Publisher: American Medical Association
Language: English
Date published: 2011
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094327802771

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