Characterizing the cancer genome in lung adenocarcinoma.
Somatic alterations in cellular DNA underlie almost all human cancers. The prospect of targeted therapies and the development of high-resolution, genome-wide approaches are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in approximately 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.
Weir
Barbara A
BA
Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Woo
Michele S
MS
Getz
Gad
G
Perner
Sven
S
Ding
Li
L
Beroukhim
Rameen
R
Lin
William M
WM
Province
Michael A
MA
Kraja
Aldi
A
Johnson
Laura A
LA
Shah
Kinjal
K
Sato
Mitsuo
M
Thomas
Roman K
RK
Barletta
Justine A
JA
Borecki
Ingrid B
IB
Broderick
Stephen
S
Chang
Andrew C
AC
Chiang
Derek Y
DY
Chirieac
Lucian R
LR
Cho
Jeonghee
J
Fujii
Yoshitaka
Y
Gazdar
Adi F
AF
Giordano
Thomas
T
Greulich
Heidi
H
Hanna
Megan
M
Johnson
Bruce E
BE
Kris
Mark G
MG
Lash
Alex
A
Lin
Ling
L
Lindeman
Neal
N
Mardis
Elaine R
ER
McPherson
John D
JD
Minna
John D
JD
Morgan
Margaret B
MB
Nadel
Mark
M
Orringer
Mark B
MB
Osborne
John R
JR
Ozenberger
Brad
B
Ramos
Alex H
AH
Robinson
James
J
Roth
Jack A
JA
Rusch
Valerie
V
Sasaki
Hidefumi
H
Shepherd
Frances
F
Sougnez
Carrie
C
Spitz
Margaret R
MR
Tsao
Ming-Sound
MS
Twomey
David
D
Verhaak
Roel G W
RG
Weinstock
George M
GM
Wheeler
David A
DA
Winckler
Wendy
W
Yoshizawa
Akihiko
A
Yu
Soyoung
S
Zakowski
Maureen F
MF
Zhang
Qunyuan
Q
Beer
David G
DG
Wistuba
Ignacio I
II
Watson
Mark A
MA
Garraway
Levi A
LA
Ladanyi
Marc
M
Travis
William D
WD
Pao
William
W
Rubin
Mark A
MA
Gabriel
Stacey B
SB
Gibbs
Richard A
RA
Varmus
Harold E
HE
Wilson
Richard K
RK
Lander
Eric S
ES
Meyerson
Matthew
M
D000230:Adenocarcinoma / Q000235:genetics*; D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D005784:Gene Amplification / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D019656:Loss of Heterozygosity / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000090063:Proto-Oncogene Mas; D034622:RNA Interference; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; C000715470:MAS1 protein, human; C411875:MBIP protein, human; C000614412:NKX2-1 protein, human; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors