The p19^INK4D Cyclin dependent kinase inhibitor gene is altered in osteosarcoma

Abstract

Inhibition of cyclin dependent kinases (CDK) by cyclin dependent kinase inhibitors (CDKI) blocks cell cycle progression and inhibits cellular proliferation. The archetypical member of the INK4 CDKI family, p16^INK4A (also called CDKN2), is a tumor suppressor frequently deleted or mutated in certain neoplasms and many cell lines. Because p19^INK4D has strong structural and functional similarity to p16^INK4A, we have assessed its role as a tumor suppressor. This was accomplished by screening the p19^INK4D coding region for mutations, deletions and rearrangements in sarcomas and non-small cell lung cancers. Alterations of the p19^INK4D gene were found in samples from five of 67 (7%) patients with osteosarcomas and none were found in other types of sarcomas or in lung cancers. Five osteosarcoma samples had Southern blot patterns 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 band revealed a one base insertion causing a frameshift beginning with codon 27. In summary, these studies found alterations affecting the p19^INK4D gene in a small but significant number of osteosarcomas. Presumably, abnormalities of this gene contribute to the development of cancer of bone cells.