Targeting DNA Damage Repair In Childhood Brain Tumors

Scientists in Japan have analyzed the chromosomes of brain tumors and discovered an inhibitor molecule that could be used in the treatment of childhood brain cancer.

AsianScientist (Jan. 2, 2018) – In a study published in the Journal of National Care Institute, scientists in Japan have scrutinized the chromosomal defects that occur in childhood brain cancer and identified an inhibitor that could be used to treat brain tumors.

Neuroblastoma (NB) is the most common solid tumor found in children. Immature nerve cells typically found in the embryo or fetus are responsible for the development of these brain tumors. Several genome alterations in NB have been reported—the deletion of the long arm of chromosome 11 (11q deletion) is one of the most frequent events in aggressive NB. In the past two decades, despite extensive efforts to identify the genes associated with 11q aberrations in NB, definitive answers are still unclear.

Earlier studies have highlighted the importance of the DNA damage response (DDR) in NB. In this study, researchers at the Tokyo Medical and Dental University (TMDU) investigated the roles of ATM and other DDR-associated molecules located in 11q.

“The protein ATM, encoded by the ATM gene, is a master regulator of DDR, and is crucial for the maintenance of genome integrity. When DNA damage occurs in genes that play important roles in the DDR itself, the checkpoint pathway is compromised, contributing to the formation of cancer,” explained Associate Professor Masatoshi Takagi of TMDU, who is lead author of the study. “Among 237 fresh tumor samples from the patients, we found ATM, MRE11A, H2AFX, and/or CHEK1 gene loss or imbalance in 11q in 20.7 percent of NB, 89.8 percent of which were stage 3 or 4 cancer.”

Furthermore, nearly half of the samples had either a single nucleotide variant, copy number alterations, or both defects in those genes. ATM-defective cells are known to exhibit dysfunctional DNA repair, which led the researchers to hypothesize that poly (ADP-ribose) polymerase (PARP) inhibitors may be effective in arresting NB growth. Indeed, the team found that 83.3 percent of NB-derived cell lines were sensitive to PARP inhibition.

“There is much more to uncover, such as how and when the mutation of DDR-associated molecules, or loss of 11q, occurs during tumor development and progression,” said Takagi.

“It will also be important to compare the frequency of mutations in DDR-associated molecules, or 11q loss, between initial samples and relapsed or metastatic samples. Nonetheless, our present results further support the inhibition of PARP as a promising therapeutic approach for specifically targeting NB,” he added.

The article can be found at: Takagi et al. (2017) Loss of DNA Damage Response in Neuroblastoma and Utility of a PARP Inhibitor.


Source: Tokyo Medical and Dental University; Photo: Shutterstock.
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