Widespread Genetic Heterogeneity in Multiple Myeloma: Implications for Targeted Therapy

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• 作者：Jens聽G. Lohr ; Petar Stojanov ; Scott聽L. Carter ; Peter Cruz-Gordillo ; Michael聽S. Lawrence ; Daniel Auclair ; Carrie Sougnez ; Birgit Knoechel ; Joshua Gould ; Gordon Saksena ; Kristian Cibulskis ; Aaron McKenna ; Michael聽A. Chapman ; Ravid Straussman ; Joan Levy ; Louise聽M. Perkins ; Jonathan聽J. Keats ; Steven聽E. Schumacher ; Mara Rosenberg ; The Multiple Myeloma Research Consortium ; Gad Getz ; et al.
• 刊名：Cancer Cell
• 出版年：13 January, 2014
• 年：2014
• 卷：25
• 期：1
• 页码：91-101
• 全文大小：2996 K

文摘

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lass="h3">Summary

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聽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.