Clonal evolution in relapsed acute myeloid leukemia revealed by whole genome sequencing

Li Ding; Michael H Tomasson; Timothy J Ley; David E Larson; Christopher A Miller; Daniel C Koboldt; John S Welch; Julie K Ritchey; Margaret A Young; Tamara Lamprecht; Michael D McLellan; Joshua F McMichael; John W Wallis; Charles Lu; Dong Shen; Christopher C Harris; David J Dooling; Robert S Fulton; Lucinda L Fulton; Heather Schmidt; Ken Chen; Joelle Kalicki-Veizer; Vincent J Magrini; Lisa Cook; Sean D McGrath; Tammi L Vickery; Michael C Wendl; Sharon Heath; Mark A Watson; Daniel C Link; William D Shannon; Jacqueline E Payton; Shashikant Kulkarni; Peter Westervelt; Matthew J Walter; Timothy A Graubert; Elaine R Mardis; Richard K Wilson; John F DiPersio

doi:10.1038/nature10738

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Clonal evolution in relapsed acute myeloid leukemia revealed by whole genome sequencing

Journal article

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Peer reviewed

Clonal evolution in relapsed acute myeloid leukemia revealed by whole genome sequencing

Li Ding, Michael H Tomasson, Timothy J Ley, David E Larson, Christopher A Miller, Daniel C Koboldt, John S Welch, Julie K Ritchey, Margaret A Young, Tamara Lamprecht, …

Nature (London), Vol.481(7382), pp.506-510

01/26/2012

DOI: 10.1038/nature10738

PMCID: PMC3267864

PMID: 22237025

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Abstract

Most patients with acute myeloid leukemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level 1 , 2 . To determine the mutational spectrum associated with relapse, we sequenced the primary tumor and relapse genomes from 8 AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to precisely define clonality and clonal evolution patterns at relapse. Besides discovering novel, recurrently mutated genes (e.g. WAC , SMC3 , DIS3 , DDX41 , and DAXX ) in AML, we found two major clonal evolution patterns during AML relapse: 1) the founding clone in the primary tumor gained mutations and evolved into the relapse clone, or 2) a subclone of the founding clone survived initial therapy, gained additional mutations, and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific vs. primary tumor mutations in all 8 cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped in part by the chemotherapy that the patients receive to establish and maintain remissions.

Details

Title: Subtitle: Clonal evolution in relapsed acute myeloid leukemia revealed by whole genome sequencing
Creators: Li Ding - The Genome Institute, Washington University, St. Louis, MO, USA
Michael H Tomasson - Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, MO, USA
Timothy J Ley - The Genome Institute, Washington University, St. Louis, MO, USA
David E Larson - The Genome Institute, Washington University, St. Louis, MO, USA
Christopher A Miller - The Genome Institute, Washington University, St. Louis, MO, USA
Daniel C Koboldt - The Genome Institute, Washington University, St. Louis, MO, USA
John S Welch - Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, MO, USA
Julie K Ritchey - Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, MO, USA
Margaret A Young - Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, MO, USA
Tamara Lamprecht - Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, MO, USA
Michael D McLellan - The Genome Institute, Washington University, St. Louis, MO, USA
Joshua F McMichael - The Genome Institute, Washington University, St. Louis, MO, USA
John W Wallis - The Genome Institute, Washington University, St. Louis, MO, USA
Charles Lu - The Genome Institute, Washington University, St. Louis, MO, USA
Dong Shen - The Genome Institute, Washington University, St. Louis, MO, USA
Christopher C Harris - The Genome Institute, Washington University, St. Louis, MO, USA
David J Dooling - The Genome Institute, Washington University, St. Louis, MO, USA
Robert S Fulton - The Genome Institute, Washington University, St. Louis, MO, USA
Lucinda L Fulton - The Genome Institute, Washington University, St. Louis, MO, USA
Heather Schmidt - The Genome Institute, Washington University, St. Louis, MO, USA
Ken Chen - The Genome Institute, Washington University, St. Louis, MO, USA
Joelle Kalicki-Veizer - The Genome Institute, Washington University, St. Louis, MO, USA
Vincent J Magrini - The Genome Institute, Washington University, St. Louis, MO, USA
Lisa Cook - The Genome Institute, Washington University, St. Louis, MO, USA
Sean D McGrath - The Genome Institute, Washington University, St. Louis, MO, USA
Tammi L Vickery - The Genome Institute, Washington University, St. Louis, MO, USA
Michael C Wendl - The Genome Institute, Washington University, St. Louis, MO, USA
Sharon Heath - Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, MO, USA
Mark A Watson - Department of Pathology and Immunology, Washington University, St. Louis, MO, USA
Daniel C Link - Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, MO, USA
William D Shannon - Division of Biostatistics, Washington University, St. Louis, MO, USA
Jacqueline E Payton - Department of Pathology and Immunology, Washington University, St. Louis, MO, USA
Shashikant Kulkarni - Department of Genetics, Washington University, St. Louis, MO, USA
Peter Westervelt - Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, MO, USA
Matthew J Walter - Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, MO, USA
Timothy A Graubert - Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, MO, USA
Elaine R Mardis - The Genome Institute, Washington University, St. Louis, MO, USA
Richard K Wilson - The Genome Institute, Washington University, St. Louis, MO, USA
John F DiPersio - Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, MO, USA
Resource Type: Journal article
Publication Details: Nature (London), Vol.481(7382), pp.506-510
DOI: 10.1038/nature10738
PMID: 22237025
PMCID: PMC3267864
NLM abbreviation: Nature
ISSN: 0028-0836
eISSN: 1476-4687
Language: English
Date published: 01/26/2012
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094537902771

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