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期刊论文
CDK4 GENE AMPLIFICATION IN OSTEOSARCOMA: RECIPROCAL RELATIONSHIP WITH INK4A GENE ALTERATIONS AND MAPPING OF 12q13 AMPLICONS
Int. J, Cancer: 80, 199-204 (1999) ,-0001,():
The INK4A gene, localized to human chromosorme 9p21, encodes P16INK4A, a tumor suppressor that functions at least in part through the inhibition of CDK4, a cyclin-dependet kinase encoded by a gent at 12q13. To examine INK4A gene alterations in uncultured samples of osteosarcoma and the relationship between INK4A adn CDK4 alterations, we ana-lyzed the INK4A and CDK4 genes in 87 specimens from 79 patients. INK4A deletion and CDK4 gene amplification were determined by quantiattive Southern blot analysis. INK4A exon 2 was screened for mutation by polymerase chain reaction and single-strand comformational polymorphism analysis. Methylation at the CpG island in INK4A, associated with loss of p16INK4A expression, was assessed by Southern blot analysis using methylation-sensitive restriction enzymes. INK4A deletion (4/55) or rearrangement (1/55) was found in 5 of 55 cases. No INK4A exon 2 poitnt mutations and methyl-ation were detected. CDK4 gene amplification was found in 6 of 67 samples, but not in tumors with INK4A alteration. Amplification analysis of other genes at 12q13 (GLI, CHOP, HMGI-C and MDM2) in these 6 cases supports the view that CDK4 and MDM2 are independent targets for amplification, with variable amplification of the intervening region comtain-ing HMGI-C. Of 46 patients studied for both INK4A alterations and CDK4 amplification, the tumors in 22% contained one or the other. The prevalence of these alterations, in conjunction with the reported inactivation of RB in up to 80% of cases, suggests that genetic lesions deregulating the G1 to S cell cycle checkpoint may be an almost constant feature in the pathogenesis of osteosarcoma. Int. J. Cancer 80: 199-204, 1999.
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