CDK4 gene amplification in osteosarcoma: Reciprocal relationship with INK4A gene alterations and mapping of 12q13 amplicons Journal Article
| Authors: | Wei, G.; Lonardo, F.; Ueda, T.; Kim, T.; Huvos, A. G.; Healey, J. H.; Ladanyi, M. |
| Article Title: | CDK4 gene amplification in osteosarcoma: Reciprocal relationship with INK4A gene alterations and mapping of 12q13 amplicons |
| Abstract: | The INK4A gene, localized to human chromosome 9p21, encodes p16(INK4A), a tumor suppressor that functions at least in part through the inhibition of CDK4, a cyclin-dependent kinase encoded by a gene at 12q13. To examine INK4A gene alterations in uncultured samples of osteosarcoma and the relationship between INK4A and CDK4 alterations, we analyzed the INK4A and CDK4 genes in 87 specimens from 79 patients. INK4A deletion and CDK4 gene amplification were determined by quantitative Southern blot analysis. INK4A exon 2 was screened for mutation by polymerase chain reaction and single-strand conformational polymorphism analysis. Methylation at the CpG island in INK4A, associated with loss of p16(INK4A) 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 point mutations and methylation 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 containing 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. |
| Keywords: | osteosarcoma; adolescent; adult; child; human tissue; bone neoplasms; proto-oncogene proteins; polymerase chain reaction; gene amplification; dna methylation; gene mapping; cyclin-dependent kinase inhibitor p16; cyclin-dependent kinases; chromosome 12q; chromosome mapping; cyclin-dependent kinase 4; polymorphism, single-stranded conformational; chromosomes, human, pair 12; humans; human; male; female; priority journal; article |
| Journal Title: | International Journal of Cancer |
| Volume: | 80 |
| Issue: | 2 |
| ISSN: | 0020-7136 |
| Publisher: | John Wiley & Sons |
| Date Published: | 1999-01-18 |
| Start Page: | 199 |
| End Page: | 204 |
| Language: | English |
| DOI: | 10.1002/(sici)1097-0215(19990118)80:2<199::aid-ijc7>3.0.co;2-4 |
| PUBMED: | 9935200 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 16 August 2016 -- Source: Scopus |
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