title: Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy.
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.
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA; Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Jens G
authors.initials: JG
authors.lastname: Lohr
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA; Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Petar
authors.initials: P
authors.lastname: Stojanov
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Cruz-Gordillo
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Auclair
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.affiliation: 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.
authors.forename: Birgit
authors.initials: B
authors.lastname: Knoechel
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Gould
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
authors.forename: Gordon
authors.initials: G
authors.lastname: Saksena
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: McKenna
authors.affiliation: Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Chapman
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
authors.forename: Ravid
authors.initials: R
authors.lastname: Straussman
authors.affiliation: The Multiple Myeloma Research Foundation, 383 Main Avenue, Fifth Floor, Norwalk, CT 06581, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Levy
authors.affiliation: The Multiple Myeloma Research Foundation, 383 Main Avenue, Fifth Floor, Norwalk, CT 06581, USA.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Perkins
authors.affiliation: Translational Genomics Research Institute (TGen), 445 N. Fifth Street, Phoenix, AZ 85004, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Keats
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA; Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schumacher
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02412, USA.
authors.forename: Mara
authors.initials: M
authors.lastname: Rosenberg
authors.affiliation: 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.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: 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.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
mesh_terms: D015153:Blotting, Western; D018628:Gene Dosage; D018740:Genetic Heterogeneity; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics*; D009154:Mutation; D017422:Sequence Analysis, DNA