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PMID: 24434212 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cancer cell ·Vol. 25 ·No. 1 ·2014-01-13 ·Pages 91-101

Lohr 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, Multiple Myeloma Research Consortium, Getz G, Golub TR

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.

MeSH Terms
Blotting, Western Gene Dosage Genetic Heterogeneity Humans Multiple Myeloma/genetics Mutation Sequence Analysis, DNA
Authors & Affiliations
22 authors, click to expand affiliations / ORCID
Lohr Jens G
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA; Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
Stojanov Petar
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA; Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
Carter Scott L
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
Cruz-Gordillo Peter
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
Lawrence Michael S
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
Auclair Daniel
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
Sougnez Carrie
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
Knoechel Birgit
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.
Gould Joshua
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
Saksena Gordon
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
Cibulskis Kristian
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
McKenna Aaron
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
Chapman Michael A
Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
Straussman Ravid
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
Levy Joan
The Multiple Myeloma Research Foundation, 383 Main Avenue, Fifth Floor, Norwalk, CT 06581, USA.
Perkins Louise M
The Multiple Myeloma Research Foundation, 383 Main Avenue, Fifth Floor, Norwalk, CT 06581, USA.
Keats Jonathan J
Translational Genomics Research Institute (TGen), 445 N. Fifth Street, Phoenix, AZ 85004, USA.
Schumacher Steven E
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA; Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
Rosenberg Mara
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
Multiple Myeloma Research Consortium
Getz Gad
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.
Golub Todd R
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: [email protected].
Investigators
29 investigators, click to expand
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
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2013.12.015
Email
[email protected]
Published
2014-01-13
Pages
91-101
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC4241387
Subset
IM
Grants
NCI NIH HHS · T32 CA009172 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · 5P50CA100707-09 · United States
World Health Organization · 001 · International
NCI NIH HHS · P50 CA100707 · United States
NCI NIH HHS · U54 CA112962 · United States
Databases
dbGaP
PHS000348
External Links
PubMed source DOI: 10.1016/j.ccr.2013.12.015 PMC Full Text View journal details
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