Multiple myeloma genomes sequenced

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Initial genome sequencing and analysis of multiple myeloma

Michael A. Chapman,1, 22
Michael S. Lawrence,1
Jonathan J. Keats,2, 3
Kristian Cibulskis,1
Carrie Sougnez,1
Anna C. Schinzel,4
Christina L. Harview,1
Jean-Philippe Brunet,1
Gregory J. Ahmann,2, 3
Mazhar Adli,1, 5
Kenneth C. Anderson,3, 4
Kristin G. Ardlie,1
Daniel Auclair,3, 6
Angela Baker,7
P. Leif Bergsagel,2, 3
Bradley E. Bernstein,1, 5, 8, 9
Yotam Drier,1, 10
Rafael Fonseca,2, 3
Stacey B. Gabriel,1
Craig C. Hofmeister,3, 11
Sundar Jagannath,3, 12
Andrzej J. Jakubowiak,3, 13
Amrita Krishnan,3, 14
Joan Levy,3, 6
Ted Liefeld,1
Sagar Lonial,3, 15 Scott Mahan,1 Bunmi Mfuko,3, 6 Stefano Monti,1 Louise M. Perkins,3, 6 Robb Onofrio,1 Trevor J. Pugh,1 S. Vincent Rajkumar,3, 16 Alex H. Ramos,1 David S. Siegel,3, 17 Andrey Sivachenko,1 A. Keith Stewart,2, 3 Suzanne Trudel,3, 18 Ravi Vij,3, 19 Douglas Voet,1 Wendy Winckler,1 Todd Zimmerman,3, 20 John Carpten,7 Jeff Trent,7 William C. Hahn,1, 4, 8 Levi A. Garraway,1, 4 Matthew Meyerson,1, 4, 8 Eric S. Lander,1, 8, 21 Gad Getz1 & Todd R. Golub1, 4, 8, 9



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.



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