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Cancer Cell. 2014 Jan 13;25(1):91-101. doi: 10.1016/j.ccr.2013.12.015.

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

Author information

1
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA; Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
2
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
3
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA; Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Boston Children's Hospital, 350 Longwood Avenue, Boston, MA 02115, USA.
4
Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
5
The Multiple Myeloma Research Foundation, 383 Main Avenue, Fifth Floor, Norwalk, CT 06581, USA.
6
Translational Genomics Research Institute (TGen), 445 N. Fifth Street, Phoenix, AZ 85004, USA.
7
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA; Massachusetts General Hospital Cancer Center and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
8
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA; Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: golub@broadinstitute.org.

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.

PMID:
24434212
PMCID:
PMC4241387
DOI:
10.1016/j.ccr.2013.12.015
[Indexed for MEDLINE]
Free PMC Article

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