# Novel variants of the ATRX gene identified in MYCN non-amplified Neuroblastoma in Brazilian patients

## TL;DR

Researchers found new ATRX gene mutations in Brazilian children with a specific type of neuroblastoma, linking these mutations to more aggressive disease and potential for better prognosis.

## Contribution

Identification of novel ATRX nonsense mutations in MYCN non-amplified neuroblastoma and their association with disease aggressiveness.

## Key findings

- Two novel nonsense ATRX variants (p.Gln1670* and p.Glu1984*) were identified in Brazilian patients with advanced MYCN non-amplified neuroblastoma.
- These mutations cause loss-of-function of ATRX, leading to more aggressive disease similar to MYCN amplified neuroblastoma.
- The findings suggest ATRX mutations may influence prognosis and treatment decisions in non-amplified MYCN neuroblastoma.

## Abstract

•Inactivation of the ATRX tumor suppressor in MYCN non-amplified neuroblastoma.•ATRX mutations have been associated with complete loss of protein expression.•ATRX mutations in neuroblastoma tend to have a progressive course of disease.•ATRX mutations are associated with age at diagnosis in patients with neuroblastoma.

Inactivation of the ATRX tumor suppressor in MYCN non-amplified neuroblastoma.

ATRX mutations have been associated with complete loss of protein expression.

ATRX mutations in neuroblastoma tend to have a progressive course of disease.

ATRX mutations are associated with age at diagnosis in patients with neuroblastoma.

Neuroblastoma is one of the most common extracranial solid tumors in children and it frequently displays high heterogeneity throughout the course of the disease. It has previously been described those changes in the ATRX gene (Alpha Thalassemia/Mental Retardation, X-linked) are the most common recurring events in the indolent clinical subtype (∼30 %) of MYCN amplified neuroblastoma. There is no effective treatment for this type of neuroblastoma, which is associated with overall poor survival. On the other hand, few studies have detected an association between high-risk (stage IV) non-amplified MYCN neuroblastoma patients and mutant ATRX.

In this study, 37 tumor samples from Brazilian patients with stages I to IV MYCN non-amplified neuroblastoma, according to the International Neuroblastoma Staging System (INSS), were analyzed using the panel Oncomine™ Childhood Cancer Research Assay.

The authors found two older children (NB1 and NB2) with advanced MYCN non-amplified neuroblastoma carried each one of the two following novel nonsense ATRX variants (p.Gln1670* or p.Glu1984*). These variants created a stop codon in the helicase domain of the ATRX gene, leading to ATRX loss-of-function. These mutations were confirmed by Sanger sequencing and the protein loss-of-function was confirmed by immunohistochemistry. The finding of these heterozygous mutations in two patients with MYCN non-amplified neuroblastoma deserves further investigation. Thus, the authors analyzed each of these cases to better understand how these mutations may be related to disease severity and prognosis.

ATRX loss-of-function from p.Gln1670* or p.Glu1984* mutations turn MYCN non-amplified neuroblastoma more aggressive and similar to what is seen in MYCN amplified neuroblastoma. This information may help clinical decision-making and facilitate establishing an accurate prognosis for patients with MYCN non-amplified neuroblastoma.