PubMed · 10916843
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M Latour Brinza, B Branger, F Vecina, J P Balducchi, C Granolleras, R Oulès, J Fourcade. 2000. [Shock? Stop!].. https://doi.org/10.1016/s0248-8663(00)89257-7
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Deletions of chromosome 3p are frequent in many types of neoplasia including neural crest tumours such as neuroblastoma (NB) and phaeochromocytoma. Recently we isolated several candidate tumour suppressor genes (TSGs) from a 120 kb critical interval at 3p21.3 defined by overlapping homozygous deletions in lung and breast tumour lines. Although mutation analysis of candidate TSGs in lung and breast cancers revealed only rare mutations, expression of one of the genes (RASSF1A) was absent in the majority of lung tumour cell lines analysed. Subsequently methylation of a CpG island in the promoter region of RASSF1A was demonstrated in a majority of small cell lung carcinomas and to a lesser extent in non-small cell lung carcinomas. To investigate the role of 3p TSGs in neural crest tumours, we (a) analysed phaeochromocytomas for 3p allele loss (n=41) and RASSF1A methylation (n=23) and (b) investigated 67 neuroblastomas for RASSF1A inactivation. 46% of phaeochromocytomas showed 3p allele loss (38.5% at 3p21.3). RASSF1A promoter region hypermethylation was found in 22% (5/23) of sporadic phaeochromocytomas and in 55% (37/67) of neuroblastomas analysed but RASSF1A mutations were not identified. In two neuroblastoma cell lines, methylation of RASSF1A correlated with loss of RASSF1A expression and RASSF1A expression was restored after treatment with the demethylating agent 5-azacytidine. As frequent methylation of the CASP8 gene has also been reported in neuroblastoma, we investigated whether RASSF1A and CASP8 methylation were independent or related events. CASP8 methylation was detected in 56% of neuroblastomas with RASSF1A methylation and 17% without RASSF1A methylation (P=0.0031). These results indicate that (a) RASSF1A inactivation by hypermethylation is a frequent event in neural crest tumorigenesis, particularly neuroblastoma, and that RASSF1A is a candidate 3p21.3 neuroblastoma TSG and (b) a subset of neuroblastomas may be characterized by a CpG island methylator phenotype.
The pediatric tumor neuroblastoma is characterized by a very variable, and at times unpredictable, pattern of clinical behavior, ranging from a benign localized tumor to an aggressive malignancy with poor prognosis. Standard clinical and pathological assessments do not always differentiate reliably between tumor subtypes and, therefore, genetic markers are now playing an increasingly important role in treatment decisions. MYCN oncogene amplification, for example, provides a useful marker of poor prognosis. However, less than one-half of all patients who present with, or who later develop, metastatic disease show MYCN amplification. Consequently, the identification of characteristic patterns of genetic alteration in the remaining tumors is of importance. In this report, we describe two new cell lines that we have established from metastatic, non-MYCN amplified, advanced stage neuroblastomas. These cell lines show a number of features in common, including unbalanced translocation between 11q and 17q, loss of 3p, 4p and 11q and gain of 17q. Therefore, they provide a valuable resource for the characterization of genetic pathways leading to aggressive tumor growth in non-MYCN amplified neuroblastomas.
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