Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma.
Comprehensive knowledge of the genomic alterations that underlie cancer is a critical foundation for diagnostics, prognostics, and targeted therapeutics. Systematic efforts to analyze cancer genomes are underway, but the analysis is hampered by the lack of a statistical framework to distinguish meaningful events from random background aberrations. Here we describe a systematic method, called Genomic Identification of Significant Targets in Cancer (GISTIC), designed for analyzing chromosomal aberrations in cancer. We use it to study chromosomal aberrations in 141 gliomas and compare the results with two prior studies. Traditional methods highlight hundreds of altered regions with little concordance between studies. The new approach reveals a highly concordant picture involving approximately 35 significant events, including 16-18 broad events near chromosome-arm size and 16-21 focal events. Approximately half of these events correspond to known cancer-related genes, only some of which have been previously tied to glioma. We also show that superimposed broad and focal events may have different biological consequences. Specifically, gliomas with broad amplification of chromosome 7 have properties different from those with overlapping focalEGFR amplification: the broad events act in part through effects on MET and its ligand HGF and correlate with MET dependence in vitro. Our results support the feasibility and utility of systematic characterization of the cancer genome.
Beroukhim
Rameen
R
Broad Institute, Massachusetts Institute of Technology and Harvard University, 7 Cambridge Center, Cambridge, MA 02142, USA.
Getz
Gad
G
Nghiemphu
Leia
L
Barretina
Jordi
J
Hsueh
Teli
T
Linhart
David
D
Vivanco
Igor
I
Lee
Jeffrey C
JC
Huang
Julie H
JH
Alexander
Sethu
S
Du
Jinyan
J
Kau
Tweeny
T
Thomas
Roman K
RK
Shah
Kinjal
K
Soto
Horacio
H
Perner
Sven
S
Prensner
John
J
Debiasi
Ralph M
RM
Demichelis
Francesca
F
Hatton
Charlie
C
Rubin
Mark A
MA
Garraway
Levi A
LA
Nelson
Stan F
SF
Liau
Linda
L
Mischel
Paul S
PS
Cloughesy
Tim F
TF
Meyerson
Matthew
M
Golub
Todd A
TA
Lander
Eric S
ES
Mellinghoff
Ingo K
IK
Sellers
William R
WR
D045744:Cell Line, Tumor; D002869:Chromosome Aberrations / Q000706:statistics & numerical data*; D003627:Data Interpretation, Statistical; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011336:Probability