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Blood. 2016 Jul 7;128(1):e1-9. doi: 10.1182/blood-2015-11-683334. Epub 2016 Apr 27.

Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies.

Author information

1
Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Department of Haematology, Haemato-oncology Diagnostic Service, Cambridge University Hospitals National Health Service Trust, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom;
2
Instituto de Biomedicina y Biotecnología de Cantabria, Cantabria, Spain;
3
Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom;
4
Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Division of Haematology, Fondazione IRCCS Istituto Nazionale dei Tumori, University of Milan, Milan, Italy;
5
Cancer Molecular Diagnosis Laboratory, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom;
6
Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; National Research Council, Institute of Genetics and Biophysics, Naples, Italy;
7
Department of Haematology, Haemato-oncology Diagnostic Service, Cambridge University Hospitals National Health Service Trust, Cambridge, United Kingdom;
8
Agilent Technologies, Cheadle, United Kingdom;
9
Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom;
10
Department of Haematology, University of Cambridge, Cambridge, United Kingdom;
11
Department of Haematology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain;
12
Department of Haematology, Haemato-oncology Diagnostic Service, Cambridge University Hospitals National Health Service Trust, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom; Cambridge Institute for Medical Research, Cambridge, United Kingdom; Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom;
13
The Center for the Study of Haematological Malignancies, Nicosia, Cyprus; The Karaiskakio Foundation, Nicosia, Cyprus;
14
Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany; German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany;
15
Department of Haematology, PathWest/Sir Charles Gairdner Hospital, Perth, Australia; and Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia.
16
Department of Haematology, Haemato-oncology Diagnostic Service, Cambridge University Hospitals National Health Service Trust, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom;

Abstract

The diagnosis of hematologic malignancies relies on multidisciplinary workflows involving morphology, flow cytometry, cytogenetic, and molecular genetic analyses. Advances in cancer genomics have identified numerous recurrent mutations with clear prognostic and/or therapeutic significance to different cancers. In myeloid malignancies, there is a clinical imperative to test for such mutations in mainstream diagnosis; however, progress toward this has been slow and piecemeal. Here we describe Karyogene, an integrated targeted resequencing/analytical platform that detects nucleotide substitutions, insertions/deletions, chromosomal translocations, copy number abnormalities, and zygosity changes in a single assay. We validate the approach against 62 acute myeloid leukemia, 50 myelodysplastic syndrome, and 40 blood DNA samples from individuals without evidence of clonal blood disorders. We demonstrate robust detection of sequence changes in 49 genes, including difficult-to-detect mutations such as FLT3 internal-tandem and mixed-lineage leukemia (MLL) partial-tandem duplications, and clinically significant chromosomal rearrangements including MLL translocations to known and unknown partners, identifying the novel fusion gene MLL-DIAPH2 in the process. Additionally, we identify most significant chromosomal gains and losses, and several copy neutral loss-of-heterozygosity mutations at a genome-wide level, including previously unreported changes such as homozygosity for DNMT3A R882 mutations. Karyogene represents a dependable genomic diagnosis platform for translational research and for the clinical management of myeloid malignancies, which can be readily adapted for use in other cancers.

Comment in

PMID:
27121471
PMCID:
PMC4937362
DOI:
10.1182/blood-2015-11-683334
[Indexed for MEDLINE]
Free PMC Article

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