Allelic imbalance on chromosome 2q and alterations of the caspase 8 gene in neuroblastoma

We previously reported a high incidence of loss of heterozygosity (LOH) on chromosome 2q33 in neuroblastoma (NB), observed in various types of human c ancers including lung cancer, head and neck cancer and follicular thyroid c arcinoma. To better elucidate the role of chromosome 20 aberrations in NE, we examined common allelic imbalance (AI) regions on chromosome 20 in 82 NE patients using 10 polymorphic microsatellite markers. AI on 20 was detecte d in 26 (32%) of 82 NE cases. There was a distinct common AI region between the D2S115 and D2S307 markers on 2q33, The distance between these markers was about 2.0 cM, Recently, the caspase 8 and caspase 10 genes, both of whi ch encode cystein protease, were mapped to chromosome 2q33, Since the commo n AI region on 2q33 includes the caspase 8 and caspase 10 genes, the altera tions of these genes were examined further. Absent or reduced expression of caspase 8 and caspase 10 were found in 19 (70%) of 27 and two (7%) of 27 N E cell lines by reverse transcription-polymerase chain reaction, respective ly. A missense mutation was detected at codon 96, GCT (Alanine) to GTT (Val ine), of the caspase 8 gene in one of the NE cell lines lacking caspase 8 e xpression. Thirteen (68%) of 19 cell lines lacking caspase 8 expression dis played methylation of the CpG island of the caspase 8 gene, whereas only on e (13%) of eight cell lines with caspase 8 expression showed caspase 8 meth ylation (P=0.031), Furthermore, there was significant association between A l at 2q33 and loss of caspase 8 expression (P=0.026), These results indicat ed that there was a tumor suppressor gene in the common AI region on chromo some 2q33 involved in the pathogenesis of a subset of NE. It is possible th at the caspase 8 gene is one of the candidate tumor suppressor genes for NE and inactivation of this gene plays an important role in the tumorigenesis of NE through mainly its methylation.