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

Author

Lohr, Jens, Stojanov, Petar, Carter, Scott, Cruz-Gordillo, Peter, Lawrence, Michael, Auclair, Daniel, Sougnez, Carrie, Knoechel, Birgit, Gould, Joshua, Saksena, Gordon, Cibulskis, Kristian, McKenna, Aaron, Chapman, Michael, Straussman, Ravid, Levy, Joan, Perkins, Louise, Keats, Jonathan, Schumacher, Steven, Rosenberg, Mara, Getz, Gad, and Golub, Todd

Subjects
Blotting, Western, Gene Dosage, Genetic Heterogeneity, Humans, Multiple Myeloma, Mutation, Sequence Analysis, DNA
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.

Published
2014

3. Widespread Genetic Heterogeneity in Multiple Myeloma: Implications for Targeted Therapy

Author

Anderson, Kenneth C., Richardson, Paul, Krishnan, Amrita, Lonial, Sagar, Kaufman, Jonathan, Siegel, David S., Vesole, David H., Roy, Vivek, Rivera, Candido E., Rajkumar, S. Vincent, Kumar, Shaji, Fonseca, Rafael, Ahmann, Greg J., Bergsagel, P. Leif, Stewart, A. Keith, Hofmeister, Craig C., Efebera, Yvonne A., Jagannath, Sundar, Chari, Ajai, Trudel, Suzanne, Reece, Donna, Wolf, Jeffrey, Martin, Thomas, Zimmerman, Todd, Rosenbaum, Cara, Jakubowiak, Andrzej J., Lebovic, Daniel, Vij, Ravi, Stockerl-Goldstein, Keith, Lohr, Jens G., Stojanov, Petar, Carter, Scott L., Cruz-Gordillo, Peter, Lawrence, Michael S., Auclair, Daniel, Sougnez, Carrie, Knoechel, Birgit, Gould, Joshua, Saksena, Gordon, Cibulskis, Kristian, McKenna, Aaron, Chapman, Michael A., Straussman, Ravid, Levy, Joan, Perkins, Louise M., Keats, Jonathan J., Schumacher, Steven E., Rosenberg, Mara, Getz, Gad, and Golub, Todd R.

Published
2014
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