Abstract
The identification of tumor-suppressor genes in solid tumors by classical cancer genetics methods is difficult and slow. We combined nonsense-mediated RNA decay microarrays1 and array-based comparative genomic hybridization2,3 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.
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Acknowledgements
We thank P. Meltzer, G. Batist, M. Kandouz, J. Khan, I. Andrulis, N. Gokgoz and E. Bruckheimer for discussions; J. Lueders, M. White and R. Autio for technical assistance; and the Sequencing Core in TGen for their services.
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Supplementary information
Supplementary Fig. 1
Chromosome specific CGH microarray plots for DU 145 cell line and PC3 cell line. (PDF 175 kb)
Supplementary Fig. 2
Sequence traces of the eight EPHB2 mutations. (PDF 5 kb)
Supplementary Table 1
Silent mutations in the EphB2 coding region. (PDF 2 kb)
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Huusko, P., Ponciano-Jackson, D., Wolf, M. et al. Nonsense-mediated decay microarray analysis identifies mutations of EPHB2 in human prostate cancer. Nat Genet 36, 979–983 (2004). https://doi.org/10.1038/ng1408
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DOI: https://doi.org/10.1038/ng1408
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