UC San Diego

Despite considerable research into the etiology of neuroblastoma, the molecular basis of this disease has remained elusive. In contrast to the absence of expression of the known tumor suppressor CDKN2A (also known as p16 and INK4A) in a wide variety of tumor types we have found in previous studies that CDKN2A protein is paradoxically highly expressed in many advanced stage neuroblastomas and unrelated to RBI status. In the present study, we sought to identify the mechanistic relationships that might influence CDKN2A expression and negate its influence on tumor cell proliferation. In this regard, we examined the role of the tumor-suppressor gene CDKNIB (also known as p27 and Kip1) and the oncogene ID2 in relationship to CDKN2A expression, MYCN amplification, and neuroblastoma pathogenesis in 17 neuroblastoma cell lines and 129 samples of primary tumors of all stages. All neuroblastoma cell lines expressed the ID2 transcript and protein. However, although the majority of primary neuroblastomas also expressed the ID2 transcript, expression of the ID2 protein was undetectable or only barely detectable, regardless of transcript expression. In both cell lines and primary tumors, ID2 expression was independent of both CDKN2A and MYCN expression. In primary neuroblastomas, CDKNIB protein was expressed in significantly fewer advanced-stage neuroblastomas than early-stage neuroblastomas, but its expression had no relationship with CDKN2A expression or MYCN amplification. We concluded that the paradoxical expression of CDKN2A in neuroblastoma cannot be explained by inactivation of the tumor-suppressor gene CDKNIB or overexpression of the oncogene ID2. We further concluded that ID2 is not a target of MYCN regulation nor is it a prognostic factor for neuroblastoma. Finally, the loss of CDKNIB in advanced-stage neuroblastoma suggests this protein may play a role in the neuroblastoma disease process. (C) 2004 Wiley-Liss, Inc.