THE P19(INK4D) CYCLIN-DEPENDENT KINASE INHIBITOR GENE IS ALTERED IN OSTEOSARCOMA

Inhibition of cyclin dependent kinases (CDK) by cyclin dependent kinas e inhibitors (CDKI) blocks cell cycle progression and inhibits cellula r proliferation. The archetypical member of the INK4 CDKI family, p16( INK4A) (also called CDKN2), is a tumor suppressor frequently deleted o r mutated in certain neoplasms and many cell lines. Because p19(INK4D) has strong structural and functional similarity to p16(INK4A), We hav e assessed its role as a tumor suppressor. This was accomplished by sc reening the p19(INK4D) coding region for mutations, deletions and rear rangements in sarcomas and non-small cell lung cancers. Alterations of the p19(INK4D) gene were found in samples from five of 67 (7%) patien ts with osteosarcomas and none were found in other types of sarcomas o r in lung cancers. Five osteosarcoma samples had Southern blot pattern s consistent with gene rearrangement. These samples included a primary and recurrent osteosarcoma from the same patient; both with the same rearrangement. Four samples had SSCP patterns consistent with sequence alterations, sequencing determined that three were due to silent base changes and apparently polymorphisms. Sequencing the fourth shifted b and revealed a one base insertion causing a frameshift beginning with codon 27. In summary, these studies found alterations affecting the p1 9(INK4D) gene in a small but significant number of osteosarcomas. Pres umably, abnormalities of this gene contribute to the development of ca ncer of bone cells.