Initial genome sequencing and analysis of multiple myeloma

• Published in: Nature (London) Vol. 471; no. 7339; pp. 467 - 472
• Main Authors: Chapman, Michael A., Lawrence, Michael S., Keats, Jonathan J., Cibulskis, Kristian, Sougnez, Carrie, Schinzel, Anna C., Harview, Christina L., Brunet, Jean-Philippe, Ahmann, Gregory J., Adli, Mazhar, Anderson, Kenneth C., Ardlie, Kristin G., Auclair, Daniel, Baker, Angela, Bergsagel, P. Leif, Bernstein, Bradley E., Drier, Yotam, Fonseca, Rafael, Gabriel, Stacey B., Hofmeister, Craig C., Jagannath, Sundar, Jakubowiak, Andrzej J., Krishnan, Amrita, Levy, Joan, Liefeld, Ted, Lonial, Sagar, Mahan, Scott, Mfuko, Bunmi, Monti, Stefano, Perkins, Louise M., Onofrio, Robb, Pugh, Trevor J., Rajkumar, S. Vincent, Ramos, Alex H., Siegel, David S., Sivachenko, Andrey, Stewart, A. Keith, Trudel, Suzanne, Vij, Ravi, Voet, Douglas, Winckler, Wendy, Zimmerman, Todd, Carpten, John, Trent, Jeff, Hahn, William C., Garraway, Levi A., Meyerson, Matthew, Lander, Eric S., Getz, Gad, Golub, Todd R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24-03-2011; Nature Publishing Group
• Subjects: 631/1647/514; 692/420/2489/68; 692/699/67/1990/804; Amino Acid Sequence; Biological and medical sciences; Blood Coagulation - genetics; Cancer; CpG Islands - genetics; Development and progression; DNA Mutational Analysis; DNA Repair - genetics; DNA sequencing; Exons - genetics; Exosome Multienzyme Ribonuclease Complex; Genetic aspects; Genetics; Genome, Human - genetics; Genomes; Genomics; Hematologic and hematopoietic diseases; Histones - metabolism; Homeodomain Proteins - genetics; Homeostasis; Homeostasis - genetics; Humanities and Social Sciences; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Kinases; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Mass spectrometry; Medical sciences; Methods; Methylation; Models, Molecular; Molecular Sequence Data; multidisciplinary; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - enzymology; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Mutation; Mutation - genetics; NF-kappa B - metabolism; Nucleotide sequencing; Oncogenes - genetics; Open Reading Frames - genetics; Pathogenesis; Protein Biosynthesis - genetics; Protein Conformation; Proteins; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Ribonucleases - chemistry; Ribonucleases - genetics; RNA Processing, Post-Transcriptional - genetics; Science; Science (multidisciplinary); Signal Transduction - genetics; Transcription, Genetic - genetics; United States; Immunopathology; Immunoglobulinopathy; Lymphoproliferative syndrome; Malignant hemopathy; Plasmacytoma; Genome; Myeloma; Genetic determinism; Cancer
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature09837

Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.
BRAF and other links to multiple myeloma
Multiple myeloma, a malignancy of plasma cells, remains incurable and is poorly understood. Chapman
et al
. have used next-generation sequencing to compare 38 multiple myeloma genomes with those of normal cells from the same patients. The disease involves mutations of genes with roles in protein translation, histone methylation and blood coagulation. In terms of clinically relevant findings, unexpected activating mutations were found in the kinase BRAF, inhibitors of which have recently shown dramatic clinical activity. This suggests that BRAF inhibitors should be evaluated in patients with BRAF-mutated multiple myeloma.
Multiple myeloma, a malignancy of plasma cells, remains incurable and is poorly understood. Using next-generation sequencing of several multiple myeloma genomes reveals that this disease involves mutations of genes involved in protein translation, histone methylation and blood coagulation. The study suggests that BRAF inhibitors should be evaluated in multiple myeloma clinical trials.