AMONG GENES INVOLVED IN THE RB DEPENDENT CELL-CYCLE REGULATORY CASCADE, THE P16 TUMOR-SUPPRESSOR GENE IS FREQUENTLY LOST IN THE EWING FAMILY OF TUMORS

The pRB cell cycle regulatory cascade is frequently perturbed in neopl asia by overexpression of a component of the pRB-phosphorylating cycli n D1/CDK4 complex or by inactivation of pRB or the CDK4 inhibitors p16 and p15, We investigated the status and expression of p16, p15, CCND1 , CDK4 and RE genes in the Ewing family of tumors, P16 loss was observ ed in 8 of 27 tumors (30%) and in 12 of 23 (52%) tumor cell lines from unrelated patients, There were no discrepancies in the p16 status bet ween primary tumors and the corresponding cell lines and between cell Lines established from consecutive tumor samples, p15 was codeleted in most cases but p15 mRNA was absent also in cell lines retaining the g ene, In addition, posttranscriptional p16 inactivation was observed in two cases, Although no evidence for CDK4 or CCND1 amplification was o btained, expression of these genes varied considerably in the cell lin es in a case specific manner, In wild-type p16 cell lines, pRB express ion was lost in one case, Our data indicate that, despite the absence of cytogenetically detectable 9p21 chromosomal aberrations, p16 deleti ons constitute the most frequent secondary molecular aberration in Ewi ng tumors so far, These results are discussed in the context of the st age of disease and the clinical outcome of the patients, The potential prognostic impact of these findings remains to be further evaluated.