1p aberrations and prognostic variables in neuroblastoma

Aim of this project is to identify genetic factors of neuroblastoma development and to establish new prognostic variables that help to choose the appropriate therapy intensity. Neuroblastoma, the most common cancer in infancy, exhibits patterns of clinical behavior ranging from rapid progression to spontaneous regression. In light of this heterogeneity, understanding the biologic behavior of an individual tumor is critical for the selection of risk-adapted therapies. The current risk stratification allows classification of tumors into subsets with distinct biological features. However, misclassification occurs in all subsets with the consequence of treatment failure, suggesting that additional parameters are needed to predict the biological course of the disease.

Deletions within 1p occur in approximately 30% of all neuroblastomas and it is widely assumed that distal 1p harbors neuroblastoma-related genetic information. We considerably narrowed down a 1p36.3 smallest region of overlapping deletions (Bauer et al. 2001, Genes Chromosomes Cancer 31:228) that encompasses two genes, FLJ10737 and CAMTA1. Sequence analysis led to the identification of coding CAMTA1 variants (Henrich et al. 2006, Eur J Cancer, in press) the functional significance of which is currently tested.

A new prognostic marker was identified analyzing CAMTA1-expression in neuroblastoma patient cohorts via real time RT-PCR and cDNA-Microarray-Analysis: Low CAMTA1-expression is significantly associated with variables of poor prognosis like advanced tumor stage or amplified MYCN oncogene. Moreover, low CAMTA1 expression characterizes tumors of patients with poor outcome (Figure 1). Multivariate survival analysis identified CAMTA1 expression as a predictor variable that is independent of the tested established prognostic markers (Henrich et al. 2006, Clin Cancer Res 12:131).

Taken together, our data suggest that (i) CAMTA1 expression represents a new powerful prognostic variable, which may improve current risk stratification models for neuroblastoma (ii) CAMTA1 is a strong candidate for the 1p36 gene being involved in the development of neuroblastoma. The validation of these hypotheses is the aim of ongoing analyses.