Hematologic Disease Laboratory, Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
Medical Oncology Department, Pediatric Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
Cancer Med. 2022 Apr;11(8):1837-1849. doi: 10.1002/cam4.4583. Epub 2022 Feb 9.
This study aimed to better understand the prognostic effect of multiple genetic markers and identify more subpopulations at ultra high risk of poor outcome in bone marrow (BM) metastatic neuroblastoma (NB).
We screened the MYCN, 1p36 and 11q23 loss of heterozygosity (LOH) statuses of 154 patients by interphase fluorescence in situ hybridization of BM cells. The clinical characteristics of patients with the three markers and their associations with prognosis were analysed.
MYCN amplification and LOH at 1p36 and 11q23 were identified in 16.2%, 33.1% and 30.5% of patients, respectively. There were strong associations between MYCN amplification and 1p36 LOH as well as 11q23 LOH. Both MYCN amplification and 1p36 LOH were strongly associated with high levels of lactate dehydrogenase (LDH) and neuron-specific enolase, more than 3 metastatic organs, and more events. 11q23 LOH occurred mainly in patients older than 18 months, and those who had high LDH levels. In univariate analysis, patients with MYCN amplification had poorer prognosis than those without. Patients with 1p36 LOH had a 3-year event-free survival (EFS) and overall survival lower than those without. 11q23 LOH was associated with poorer EFS only for patients without MYCN amplification. In a multivariate model, MYCN amplification was independently associated with decreased EFS in all cohorts. 11q23 LOH was an independent prognostic factor for patients without MYCN amplification, whereas 1p36 LOH was not an independent marker regardless of MYCN amplification. Compared with all cohorts, patients with both MYCN amplification and 1p36 LOH had the worst outcome and clinical features.
Patients with both MYCN amplification and 1p36LOH had the worst survival rate, indicating an ultra high-risk group. Our results may be applied in clinical practice for accurate risk stratification in future studies.
本研究旨在更好地了解多个遗传标志物的预后效应，并确定骨髓（BM）转移性神经母细胞瘤（NB）中预后极差的亚群。
我们通过 BM 细胞的间期荧光原位杂交筛选了 154 例患者的 MYCN、1p36 和 11q23 杂合性丢失（LOH）状态。分析了具有这三种标志物的患者的临床特征及其与预后的关系。
16.2%、33.1%和 30.5%的患者分别存在 MYCN 扩增、1p36 LOH 和 11q23 LOH。MYCN 扩增与 1p36 LOH 和 11q23 LOH 之间存在很强的关联。MYCN 扩增和 1p36 LOH 均与高乳酸脱氢酶（LDH）和神经元特异性烯醇化酶水平、3 个以上转移器官和更多事件相关。11q23 LOH 主要发生在 18 个月以上的患者和 LDH 水平较高的患者中。在单因素分析中，MYCN 扩增的患者预后较差。有 1p36 LOH 的患者无事件生存率（EFS）和总生存率低于无 1p36 LOH 的患者。只有在没有 MYCN 扩增的患者中，11q23 LOH 与较差的 EFS 相关。在多变量模型中，MYCN 扩增是所有队列中 EFS 降低的独立相关因素。11q23 LOH 是无 MYCN 扩增患者的独立预后因素，而 1p36 LOH 无论是否存在 MYCN 扩增均不是独立标志物。与所有队列相比，同时具有 MYCN 扩增和 1p36 LOH 的患者预后最差，临床表现也最严重。
同时具有 MYCN 扩增和 1p36 LOH 的患者生存率最差，提示为超高风险组。我们的结果可能适用于临床实践，以便在未来的研究中进行更准确的风险分层。
