Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies
Por:
McKerrell, T, Moreno, T, Ponstingl, H, Bolli, N, Dias, JML, Tischler, G, Colonna, V, Manasse, B, Bench, A, Bloxham, D, Herman, B, Fletcher, D, Park, N, Quail, MA, Manes, N, Hodkinson, C, Baxter, J, Sierra, J, Foukaneli, T, Warren, AJ, Chi, JX, Costeas, P, Rad, R, Huntly, B, Grove, C, Ning, ZM, Tyler-Smith, C, Varela, I, Scott, M, Nomdedeu, J, Mustonen, V, Vassiliou, GS
Publicada:
7 jul 2016
Resumen:
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 mainstreamdiagnosis; 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.
Filiaciones:
McKerrell, T:
Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England
Cambridge Univ Hosp Natl Hlth Serv Trust, Dept Haematol, Haematooncol Diagnost Serv, Cambridge, England
Univ Cambridge, Dept Haematol, Cambridge, England
Moreno, T:
Inst Biomed & Biotecnol Cantabria, Cantabria, Spain
Ponstingl, H:
Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England
Bolli, N:
Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England
Univ Milan, Fdn IRCCS Ist Nazl Tumori, Div Haematol, Milan, Italy
Dias, JML:
Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Canc Mol Diag Lab, Cambridge, England
Tischler, G:
Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England
Colonna, V:
Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England
CNR, Inst Genet & Biophys, Naples, Italy
Manasse, B:
Cambridge Univ Hosp Natl Hlth Serv Trust, Dept Haematol, Haematooncol Diagnost Serv, Cambridge, England
Bench, A:
Cambridge Univ Hosp Natl Hlth Serv Trust, Dept Haematol, Haematooncol Diagnost Serv, Cambridge, England
Bloxham, D:
Cambridge Univ Hosp Natl Hlth Serv Trust, Dept Haematol, Haematooncol Diagnost Serv, Cambridge, England
Herman, B:
Agilent Technol, Cheadle, England
Fletcher, D:
Agilent Technol, Cheadle, England
Park, N:
Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England
Quail, MA:
Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England
Manes, N:
Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England
Univ Cambridge, Dept Haematol, Cambridge, England
Hodkinson, C:
Univ Cambridge, Dept Haematol, Cambridge, England
Baxter, J:
Univ Cambridge, Dept Haematol, Cambridge, England
Sierra, J:
Hosp Santa Creu & Sant Pau, Dept Haematol, Barcelona, Spain
Foukaneli, T:
Cambridge Univ Hosp Natl Hlth Serv Trust, Dept Haematol, Haematooncol Diagnost Serv, Cambridge, England
Warren, AJ:
Cambridge Univ Hosp Natl Hlth Serv Trust, Dept Haematol, Haematooncol Diagnost Serv, Cambridge, England
Univ Cambridge, Dept Haematol, Cambridge, England
Cambridge Inst Med Res, Cambridge, England
Univ Cambridge, Wellcome Trust Med Res Council, Cambridge Stem Cell Inst, Cambridge, England
Chi, JX:
Ctr Study Haematol Malignancies, Nicosia, Cyprus
Karaiskakio Fdn, Nicosia, Cyprus
Costeas, P:
Ctr Study Haematol Malignancies, Nicosia, Cyprus
Karaiskakio Fdn, Nicosia, Cyprus
Rad, R:
Tech Univ Munich, Klinikum Rechts Isar, Dept Med 2, Munich, Germany
German Canc Res Ctr, German Canc Consortium, Heidelberg, Germany
Huntly, B:
Cambridge Univ Hosp Natl Hlth Serv Trust, Dept Haematol, Haematooncol Diagnost Serv, Cambridge, England
Univ Cambridge, Dept Haematol, Cambridge, England
Cambridge Inst Med Res, Cambridge, England
Univ Cambridge, Wellcome Trust Med Res Council, Cambridge Stem Cell Inst, Cambridge, England
Grove, C:
PathWest Sir Charles Gairdner Hosp, Dept Haematol, Perth, WA, Australia
Univ Western Australia, Pathol & Lab Med, Perth, WA, Australia
Ning, ZM:
Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England
Tyler-Smith, C:
Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England
Varela, I:
Inst Biomed & Biotecnol Cantabria, Cantabria, Spain
Scott, M:
Cambridge Univ Hosp Natl Hlth Serv Trust, Dept Haematol, Haematooncol Diagnost Serv, Cambridge, England
Univ Cambridge, Dept Haematol, Cambridge, England
Nomdedeu, J:
Hosp Santa Creu & Sant Pau, Dept Haematol, Barcelona, Spain
Mustonen, V:
Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England
Vassiliou, GS:
Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England
Cambridge Univ Hosp Natl Hlth Serv Trust, Dept Haematol, Haematooncol Diagnost Serv, Cambridge, England
Univ Cambridge, Dept Haematol, Cambridge, England
Green Published, Bronze
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