Recurrent alterations at relapse included mutations in the putative CHD5neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target YAP.
Recurrent alterations at relapse included mutations in the putative CHD5neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target YAP.
Furthermore, low CHD5 expression is strongly associated with unfavorable clinical and biologic features as well as outcome in neuroblastomas and many other tumor types.
These findings provide insights into the regulatory role of CHD5 during neurogenesis and suggest how inactivation of this candidate tumor suppressor might contribute to neuroblastoma.
We conclude that (i) somatically acquired CHD5 mutations are rare in primary NBs, so inactivation probably occurs by deletion and epigenetic silencing; (ii) CHD5 expression and promoter methylation are associated with MYCN amplification, suggesting a possible interaction between these 2 genes; and (iii) high CHD5 expression is strongly correlated with favorable clinical/biological features and outcome.
In the present study, our results showed that genistein, an element found in soy, is an epigenetic modifier able to decrease hypermethylation levels of CHD5, and enhances the expression of CHD5 as well as p53, possibly contributing to inhibition of NB growth in vivo and tumor microvessel formation.
Among the best candidate genes predisposing to the development of neuroblastoma located in 1p36, the AJAP1 gene is the only gene present in the duplication while CHD5, TNFRSF25 and CAMTA1 are located outside of the rearrangement.
Our mutation and expression analysis in neuroblastoma cell lines, combined with expression analysis in normal tissues, putative function and prior implication in neuroblastoma pathogenesis, suggests that the most promising TSG deleted from the 1p36 SRD is CHD5, but TNFRSF25, CAMTA1 and AJAP1 are also viable candidates.