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Cancer Cell DOI:10.1016/j.ccr.2013.12.015

Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy.

Publication TypeJournal Article
Year of Publication2014
AuthorsLohr, JG, Stojanov, P, Carter, SL, Cruz-Gordillo, P, Lawrence, MS, Auclair, D, Sougnez, C, Knoechel, B, Gould, J, Saksena, G, Cibulskis, K, McKenna, A, Chapman, MA, Straussman, R, Levy, J, Perkins, LM, Keats, JJ, Schumacher, SE, Rosenberg, M, Getz, G, Golub, TR
Corporate AuthorsMultiple Myeloma Research Consortium
JournalCancer Cell
Date Published2014 Jan 13
KeywordsBlotting, Western, Gene Dosage, Genetic Heterogeneity, Humans, Multiple Myeloma, Mutation, Sequence Analysis, DNA

We performed massively parallel sequencing of paired tumor/normal samples from 203 multiple myeloma (MM) patients and identified significantly mutated genes and copy number alterations and discovered putative tumor suppressor genes by determining homozygous deletions and loss of heterozygosity. We observed frequent mutations in KRAS (particularly in previously treated patients), NRAS, BRAF, FAM46C, TP53, and DIS3 (particularly in nonhyperdiploid MM). Mutations were often present in subclonal populations, and multiple mutations within the same pathway (e.g., KRAS, NRAS, and BRAF) were observed in the same patient. In vitro modeling predicts only partial treatment efficacy of targeting subclonal mutations, and even growth promotion of nonmutated subclones in some cases. These results emphasize the importance of heterogeneity analysis for treatment decisions.


Alternate JournalCancer Cell
PubMed ID24434212
PubMed Central IDPMC4241387
Grant ListT32 CA009172 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
5P50CA100707-09 / CA / NCI NIH HHS / United States
P50 CA100707 / CA / NCI NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States
001 / / World Health Organization / International