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.
Translational Genomics Research Institute, Cancer Drug Development Laboratory, 20 Firstfield Road, Suite 110, Gaithersburg, Maryland 20878, USA.
Pia
P
Huusko
Damaris
D
Ponciano-Jackson
Maija
M
Wolf
Jeff A
JA
Kiefer
David O
DO
Azorsa
Sukru
S
Tuzmen
Don
D
Weaver
Christiane
C
Robbins
Tracy
T
Moses
Minna
M
Allinen
Sampsa
S
Hautaniemi
Yidong
Y
Chen
Abdel
A
Elkahloun
Mark
M
Basik
G Steven
GS
Bova
Lukas
L
Bubendorf
Alessandro
A
Lugli
Guido
G
Sauter
Johanna
J
Schleutker
Hilmi
H
Ozcelik
Sabine
S
Elowe
Tony
T
Pawson
Jeffrey M
JM
Trent
John D
JD
Carpten
Olli-P
OP
Kallioniemi
Spyro
S
Mousses
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