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Nonsense-mediated decay microarray analysis identifies mutations of EPHB2 in human prostate cancer 总被引:7,自引:0,他引:7
Huusko P Ponciano-Jackson D Wolf M Kiefer JA Azorsa DO Tuzmen S Weaver D Robbins C Moses T Allinen M Hautaniemi S Chen Y Elkahloun A Basik M Bova GS Bubendorf L Lugli A Sauter G Schleutker J Ozcelik H Elowe S Pawson T Trent JM Carpten JD Kallioniemi OP Mousses S 《Nature genetics》2004,36(9):979-983
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. 相似文献
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Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk 总被引:16,自引:0,他引:16
Xu J Zheng SL Komiya A Mychaleckyj JC Isaacs SD Hu JJ Sterling D Lange EM Hawkins GA Turner A Ewing CM Faith DA Johnson JR Suzuki H Bujnovszky P Wiley KE DeMarzo AM Bova GS Chang B Hall MC McCullough DL Partin AW Kassabian VS Carpten JD Bailey-Wilson JE Trent JM Ohar J Bleecker ER Walsh PC Isaacs WB Meyers DA 《Nature genetics》2002,32(2):321-325
Deletions on human chromosome 8p22-23 in prostate cancer cells and linkage studies in families affected with hereditary prostate cancer (HPC) have implicated this region in the development of prostate cancer. The macrophage scavenger receptor 1 gene (MSR1, also known as SR-A) is located at 8p22 and functions in several processes proposed to be relevant to prostate carcinogenesis. Here we report the results of genetic analyses that indicate that mutations in MSR1 may be associated with risk of prostate cancer. Among families affected with HPC, we identified six rare missense mutations and one nonsense mutation in MSR1. A family-based linkage and association test indicated that these mutations co-segregate with prostate cancer (P = 0.0007). In addition, among men of European descent, MSR1 mutations were detected in 4.4% of individuals affected with non-HPC as compared with 0.8% of unaffected men (P = 0.009). Among African American men, these values were 12.5% and 1.8%, respectively (P = 0.01). These results show that MSR1 may be important in susceptibility to prostate cancer in men of both African American and European descent. 相似文献
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Karhadkar SS Bova GS Abdallah N Dhara S Gardner D Maitra A Isaacs JT Berman DM Beachy PA 《Nature》2004,431(7009):707-712
Metastatic cancers adopt certain properties of normal cells in developing or regenerating organs, such as the ability to proliferate and alter tissue organization. We find here that activity of the Hedgehog (Hh) signalling pathway, which has essential roles in developmental patterning, is required for regeneration of prostate epithelium, and that continuous pathway activation transforms prostate progenitor cells and renders them tumorigenic. Elevated pathway activity furthermore distinguishes metastatic from localized prostate cancer, and pathway manipulation can modulate invasiveness and metastasis. Pathway activity is triggered in response to endogenous expression of Hh ligands, and is dependent upon the expression of Smoothened, an essential Hh response component that is not expressed in benign prostate epithelial cells. Monitoring and manipulating Hh pathway activity may thus offer significant improvements in diagnosis and treatment of prostate cancers with metastatic potential. 相似文献
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