Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy.
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Abstract | 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. |
Year of Publication | 2014
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Journal | Cancer Cell
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Volume | 25
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Issue | 1
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Pages | 91-101
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Date Published | 2014 Jan 13
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ISSN | 1878-3686
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URL | |
DOI | 10.1016/j.ccr.2013.12.015
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PubMed ID | 24434212
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PubMed Central ID | PMC4241387
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Grant list | T32 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
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