Expression of p27(kip1) is prognostic and independent in MYCN amplification in human neuroblastoma

Amplification of the MYCN gene is significantly associated with an unfavora ble prognosis and rapid progression in human neuroblastoma tumors. One pote ntial mechanism by which MYCN may cause these effects is by deregulating ce ll proliferation, Tissue culture experiments support a model in which MYC g enes stimulate cell cycle progression by antagonizing the function of the c ell cycle inhibitor p27(kip1). In culture, activation of MYC induces both s equestration of p27(kip1) by cyclin D complexes and its subsequent proteoly tic degradation. We have tested whether this model applies to human neurobl astoma in a retrospective study of 100 primary tumor biopsy samples from ne uroblastoma patients with a documented follow-up. Consistent with this hypo thesis, MYCN-amplified tumors express high levels of both cyclin A and prol iferating cell nuclear antigen, 2 marker proteins of cell proliferation, Fu rther, expression levels of p27(kip1) are of prognostic significance in hum an neuroblastoma patients. Similar to tissue culture systems, p27(kip1) is sequestered by cyclin D complexes in a subset of human neuroblastoma sample s. Surprisingly, however, expression levels of p27(kip1) are prognostic ind ependent of MYCN amplification, and tumors that have an amplified MYCN gene do not express elevated levels of D-type cyclins or contain significantly lower levels of p27(kip1). Our data do not support a model in which regulat ion of p27(kip1) function is an important mechanism by which amplified MYCN deregulates cell proliferation in neuroblastoma, (C) 2001 Wiley-Liss, Inc.