Nonsense-mediated decay microarray analysis identifies mutations of EPHB2 in human prostate cancer.
The identification of tumor-suppressor genes in solid tumors by classical cancer genetics methods is difficult and slow. We combined nonsense-mediated RNA decay microarrays and array-based comparative genomic hybridization for the genome-wide identification of genes with biallelic inactivation involving nonsense mutations and loss of the wild-type allele. This approach enabled us to identify previously unknown mutations in the receptor tyrosine kinase gene EPHB2. The DU 145 prostate cancer cell line, originating from a brain metastasis, carries a truncating mutation of EPHB2 and a deletion of the remaining allele. Additional frameshift, splice site, missense and nonsense mutations are present in clinical prostate cancer samples. Transfection of DU 145 cells, which lack functional EphB2, with wild-type EPHB2 suppresses clonogenic growth. Taken together with studies indicating that EphB2 may have an essential role in cell migration and maintenance of normal tissue architecture, our findings suggest that mutational inactivation of EPHB2 may be important in the progression and metastasis of prostate cancer.
Huusko
Pia
P
Translational Genomics Research Institute, Cancer Drug Development Laboratory, 20 Firstfield Road, Suite 110, Gaithersburg, Maryland 20878, USA.
Ponciano-Jackson
Damaris
D
Wolf
Maija
M
Kiefer
Jeff A
JA
Azorsa
David O
DO
Tuzmen
Sukru
S
Weaver
Don
D
Robbins
Christiane
C
Moses
Tracy
T
Allinen
Minna
M
Hautaniemi
Sampsa
S
Chen
Yidong
Y
Elkahloun
Abdel
A
Basik
Mark
M
Bova
G Steven
GS
Bubendorf
Lukas
L
Lugli
Alessandro
A
Sauter
Guido
G
Schleutker
Johanna
J
Ozcelik
Hilmi
H
Elowe
Sabine
S
Pawson
Tony
T
Trent
Jeffrey M
JM
Carpten
John D
JD
Kallioniemi
Olli-P
OP
Mousses
Spyro
S
D045744:Cell Line, Tumor; D018389:Codon, Nonsense; D004640:Emetine / Q000494:pharmacology; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000235:genetics*; D020871:RNA Stability; D036183:Receptor, EphB2 / Q000235:genetics*; D014162:Transfection
D018389:Codon, Nonsense; D036183:Receptor, EphB2; D004640:Emetine