title: A DNA target-enrichment approach to detect mutations, copy number changes and immunoglobulin translocations in multiple myeloma.
abstract: Genomic lesions are not investigated during routine diagnostic workup for multiple myeloma (MM). Cytogenetic studies are performed to assess prognosis but with limited impact on therapeutic decisions. Recently, several recurrently mutated genes have been described, but their clinical value remains to be defined. Therefore, clinical-grade strategies to investigate the genomic landscape of myeloma samples are needed to integrate new and old prognostic markers. We developed a target-enrichment strategy followed by next-generation sequencing (NGS) to streamline simultaneous analysis of gene mutations, copy number changes and immunoglobulin heavy chain (IGH) translocations in MM in a high-throughput manner, and validated it in a panel of cell lines. We identified 548 likely oncogenic mutations in 182 genes. By integrating published data sets of NGS in MM, we retrieved a list of genes with significant relevance to myeloma and found that the mutational spectrum of primary samples and MM cell lines is partially overlapping. Gains and losses of chromosomes, chromosomal segments and gene loci were identified with accuracy comparable to conventional arrays, allowing identification of lesions with known prognostic significance. Furthermore, we identified IGH translocations with high positive and negative predictive value. Our approach could allow the identification of novel biomarkers with clinical relevance in myeloma.
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Cambridge, UK.|Department of Oncology and Onco-Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, University of Milan, Milan, Italy.
authors: N
authors: 0000-0002-1018-5139
authors: N
authors: Bolli
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Cambridge, UK.
authors: Y
authors: Y
authors: Li
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Cambridge, UK.
authors: V
authors: V
authors: Sathiaseelan
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Cambridge, UK.
authors: K
authors: K
authors: Raine
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Cambridge, UK.
authors: D
authors: D
authors: Jones
authors: Department of Pathology (UOC), University of Otago, Christchurch, New Zealand.
authors: P
authors: P
authors: Ganly
authors: Division of Hematology, Fondazione IRCCS Policlinico San Matteo di Pavia, Pavia, Italy.
authors: F
authors: F
authors: Cocito
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Cambridge, UK.
authors: G
authors: G
authors: Bignell
authors: Department of Haematology, University of Cambridge, Cambridge, UK.
authors: M A
authors: MA
authors: Chapman
authors: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: A S
authors: AS
authors: Sperling
authors: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: K C
authors: KC
authors: Anderson
authors: Unité de Genomique du Myelome, Centre Hospitalier Universitaire Rangueil, Toulouse, France.|Centre de Recherche en Cancerologie de Toulouse, INSERM U1037, Toulouse, France.
authors: H
authors: H
authors: Avet-Loiseau
authors: Hematology Department, Centre de Recherche en Cancerologie Nantes-Angers Unité Mixte de Recherche INSERM 892-Centre National de la Recherche Scientifique 6299 and Institut de Recherche Therapeutique de l'Université de Nantes, Nantes, France.
authors: S
authors: S
authors: Minvielle
authors: Cancer Genome Project, Wellcome Trust Sanger Institute, Cambridge, UK.
authors: P J
authors: PJ
authors: Campbell
authors: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: N C
authors: NC
authors: Munshi
mesh_terms: D000483:Alleles; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations; D005787:Gene Frequency; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D019656:Loss of Heterozygosity; D009101:Multiple Myeloma / Q000235:genetics*; D009154:Mutation; D015203:Reproducibility of Results; D014178:Translocation, Genetic
chemical_list: D007143:Immunoglobulin Heavy Chains