11q deletion in neuroblastoma: a review of biological and clinical implications

Abstract

Deletion of the long arm of chromosome 11 (11q deletion) is one of the most frequent events that occur during the development of aggressive neuroblastoma. Clinically, 11q deletion is associated with higher disease stage and decreased survival probability. During the last 25 years, extensive efforts have been invested to identify the precise frequency of 11q aberrations in neuroblastoma, the recurrently involved genes, and to understand the molecular mechanisms of 11q deletion, but definitive answers are still unclear. In this review, it is our intent to compile and review the evidence acquired to date on 11q deletion in neuroblastoma.

Low DLG2 gene expression, a link between 11q-deleted and MYCN-amplified neuroblastoma, causes forced cell cycle progression, and predicts poor patient survival.

“…These findings are in agreement with the reviewed data by Mlakar et. al., for 11q deleted NB as they also reached the conclusion that the 11q deletion is likely going to have haploinsufficiency (9).…”

“…However, in the rare cases when patients do have both MYCN amplification and 11q LOH, the deletion point is found to be located more terminally than other 11q LOH tumors. These two common aggressive NB forms are therefore usually considered to be mutually exclusive (9). The mechanism of the mutual exclusivity remains to be determined, as the definitive identification of a single tumor suppressor gene within 11q remains elusive.…”

“…Consequently, it is accepted that the tumor suppressor gene disrupted by 11q LOH must satisfy a set of criteria based on the known clinical and genetic alterations observed, something that previous attempts at tumor suppressor characterization on 11q have also considered. The first characteristic is the inverse relation of 11q and MYCN amplification; with 11q deletion substituting the function of MYCN amplification or by MYCN amplification acting to disrupt the 11q tumor suppressor gene function (9).…”

Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma

“…The smallest region of overlap in 11q deletions has been reported between 11q14 and 11q23 (43) including genes such as CADM1 (11q23.3), and 4 genes involved in the DDR: ATM (11q22.3), CHK1 (11q24.2), MRE11 (11q21), and H2AFX (11q23.3), which have been functionally tested as candidate genes responsible for driving NB tumorigenesis [ Figure 1; (44)]. No mutation or hyper-methylation was found in the other allele of these genes in most cases (44), however loss of one copy via 11q deletion could contribute to tumorigenesis due to haploinsufficiency.…”

Prostaglandin receptor EP2 is a novel molecular target for high-risk neuroblastoma

“…whereas the deletion of the long arm of chromosome 11 (11q) that causes the development of aggressive neuroblastoma in older children often correlates with advanced disease stage, drug resistance, and decreased survival probability (2,3). Therefore, identifying new druggable targets and developing novel therapies for patients suffering from neuroblastomaparticularly those who are in high-risk category and developed resistance to current treatmentare in urgent demand.…”