HOMOZYGOUS DELETION FREQUENCY AND EXPRESSION LEVELS OF THE CDKN2 GENEIN HUMAN SARCOMAS - RELATIONSHIP TO AMPLIFICATION AND MESSENGER-RNA LEVELS OF CDK4 AND CCND1

Homozygous deletions of the putative rumour-suppressor gene CDKN2, whi ch encodes an inhibitor of cdk4, have been detected in a high percenta ge of cancer cell lines of various histological types. In the present study, 109 human sarcomas were examined for homozygous deletions and f or mRNA expression levels of the CDKN2 gene. Altogether, deletions wer e found in only eight (7%) of the cases, but, interestingly, in two (o f eight) malignant Schwannomas and in two (of five) rhabdomyosarcomas. In comparison, such deletions were seen in only one (of 21) osteosarc omas and in none of 20 MFHs and 21 liposarcomas. Notably, highly eleva ted CDKN2 mRNA levels were found in 33% of the sarcomas, whereas no de tectable transcript was present in 12 normal tissues. Amplifications o f CDK4 and CCND1 (cyclin D1) were observed in 11% and 4% of the sarcom as respectively, but never in rumours with CDKN2 deletions. The level of CDK4 mRNA expression was increased in nine tumours in addition to t he 12 samples with CDK4 amplification. Increased levels of the cyclin D1 transcript was found in 37 cases, four with and 33 without amplific ation. The data indicate that aberrations of these functionally relate d genes, or in regulation of the expression of the kinase, the activat or or the inhibitor, may participate in sarcoma development. Furthermo re, the data suggest that homozygous CDKN2 deletions may be of dissimi lar significance in different sarcoma subtypes.