Amplification of chromosomal segment 4q12 in non-small cell lung cancer.
In cancer, proto-oncogenes are often altered by genomic amplification. Here we report recurrent focal amplifications of chromosomal segment 4q12 overlapping the proto-oncogenes PDGFRA and KIT in non-small cell lung cancer (NSCLC). Single nucleotide polymorphism (SNP) array and fluorescent in situ hybridization (FISH) analysis indicate that 4q12 is amplified in 3-7% of lung adenocarcinomas and 8-10% of lung squamous cell carcinomas. In addition, we demonstrate that the NSCLC cell line NCI-H1703 exhibits focal amplification of PDGFRA and is dependent on PDGFRalpha activity for cell growth. Treatment of NCI-H1703 cells with PDGFRA-specific shRNAs or with the PDGFRalpha/KIT small molecule inhibitors imatinib or sunitinib leads to cell growth inhibition. However, these observations do not extend to NSCLC cell lines with lower-amplitude and broader gains of chromosome 4q. Together these observations implicate PDGFRA and KIT as potential oncogenes in NSCLC, but further study is needed to define the specific characteristics of those tumors that could respond to PDGFRalpha/KIT inhibitors.
Ramos
Alex H
AH
Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA.
Dutt
Amit
A
Mermel
Craig
C
Perner
Sven
S
Cho
Jeonghee
J
Lafargue
Christopher J
CJ
Johnson
Laura A
LA
Stiedl
Ann-Cathrin
AC
Tanaka
Kumiko E
KE
Bass
Adam J
AJ
Barretina
Jordi
J
Weir
Barbara A
BA
Beroukhim
Rameen
R
Thomas
Roman K
RK
Minna
John D
JD
Chirieac
Lucian R
LR
Lindeman
Neal I
NI
Giordano
Thomas
T
Beer
David G
DG
Wagner
Patrick
P
Wistuba
Ignacio I
II
Rubin
Mark A
MA
Meyerson
Matthew
M
D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002894:Chromosomes, Human, Pair 4; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*
D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha