Magalhães Gimenez Thamiris, Peralta Vanessa Pretes, Giorgi Ricardo Rodrigues, Morikawa Karina, Vince Carolina Camargo, Halley Nathalia, Siqueira Sheila Aparecida, Bendit Israel, Cristofani Lilian Maria, Filho Vicente Odone, Novak Estela Maria
Instituto do Cancer do Estado de Sao Paulo (ICESP/ITACI), São Paulo, Brazil.
Laboratório de Investigação Médica em Pediatria Clínica -Lim-36.Instituto da Criança. Hospital de Clínicas, Faculdade de Medicina, Universidade de São Paulo (HC/FMUSP), São Paulo, Brazil.
Clinics (Sao Paulo). 2025 Apr 25;80:100652. doi: 10.1016/j.clinsp.2025.100652. eCollection 2025.
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.
神经母细胞瘤是儿童最常见的颅外实体瘤之一，在疾病发展过程中常常表现出高度异质性。此前有研究表明，ATRX基因（α地中海贫血/智力发育迟缓，X连锁）的改变是MYCN扩增型神经母细胞瘤惰性临床亚型中最常见的复发性事件（约30%）。这类神经母细胞瘤尚无有效治疗方法，患者总体生存率较差。另一方面，很少有研究检测到高危（IV期）非MYCN扩增型神经母细胞瘤患者与ATRX突变之间存在关联。
在本研究中，根据国际神经母细胞瘤分期系统（INSS），对37例来自巴西的I至IV期非MYCN扩增型神经母细胞瘤患者的肿瘤样本，使用Oncomine™儿童癌症研究分析试剂盒进行分析。
作者发现两名年龄较大的患有晚期非MYCN扩增型神经母细胞瘤的儿童（NB1和NB2）分别携带以下两种新型无义ATRX变体之一（p.Gln1670或p.Glu1984）。这些变体在ATRX基因的解旋酶结构域中产生了一个终止密码子，导致ATRX功能丧失。这些突变通过桑格测序得到证实，蛋白质功能丧失通过免疫组织化学得到证实。在两名非MYCN扩增型神经母细胞瘤患者中发现这些杂合突变值得进一步研究。因此，作者对每例病例进行分析，以更好地了解这些突变与疾病严重程度和预后的关系。
p.Gln1670或p.Glu1984突变导致的ATRX功能丧失使非MYCN扩增型神经母细胞瘤更具侵袭性，类似于MYCN扩增型神经母细胞瘤。这一信息可能有助于临床决策，并有助于为非MYCN扩增型神经母细胞瘤患者建立准确的预后。
