Department of Pediatric Research, Division of Paediatric and Adolescent Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
Medical Faculty, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
PLoS One. 2022 Aug 29;17(8):e0273280. doi: 10.1371/journal.pone.0273280. eCollection 2022.
Neuroblastoma (NBL), one of the main death-causing cancers in children, is known for its remarkable genetic heterogeneity and varied patient outcome spanning from spontaneous regression to widespread disease. Specific copy number variations and single gene rearrangements have been proven to be associated with biological behavior and prognosis; however, there is still an unmet need to enlarge the existing armamentarium of prognostic and therapeutic targets. We performed whole exome sequencing (WES) of samples from 18 primary tumors and six relapse samples originating from 18 NBL patients. Our cohort consists of 16 high-risk, one intermediate, and one very low risk patient. The obtained results confirmed known mutational hotspots in ALK and revealed other non-synonymous variants of NBL-related genes (TP53, DMD, ROS, LMO3, PRUNE2, ERBB3, and PHOX2B) and of genes cardinal for other cancers (KRAS, PIK3CA, and FLT3). Beyond, GOSeq analysis determined genes involved in biological adhesion, neurological cell-cell adhesion, JNK cascade, and immune response of cell surface signaling pathways. We were able to identify novel coding variants present in more than one patient in nine biologically relevant genes for NBL, including TMEM14B, TTN, FLG, RHBG, SHROOM3, UTRN, HLA-DRB1, OR6C68, and XIRP2. Our results may provide novel information about genes and signaling pathways relevant for the pathogenesis and clinical course in high-risk NBL.
神经母细胞瘤（NBL）是儿童主要致死癌症之一，其具有显著的遗传异质性和不同的患者预后，从自发消退到广泛疾病都有。特定的拷贝数变异和单个基因重排已被证明与生物学行为和预后相关；然而，仍然需要扩大现有的预后和治疗靶点武器库。我们对 18 名 NBL 患者的 18 个原发肿瘤和 6 个复发样本进行了全外显子组测序（WES）。我们的队列包括 16 名高危患者、1 名中危患者和 1 名极低危患者。获得的结果证实了 ALK 中的已知突变热点，并揭示了其他与 NBL 相关基因（TP53、DMD、ROS、LMO3、PRUNE2、ERBB3 和 PHOX2B）和其他癌症关键基因（KRAS、PIK3CA 和 FLT3）的非同义变体。此外，GOSeq 分析确定了参与生物粘附、神经细胞-细胞粘附、JNK 级联和细胞表面信号通路免疫反应的基因。我们能够在九个与 NBL 相关的生物学上有意义的基因中鉴定出九个患者中存在的新编码变体，包括 TMEM14B、TTN、FLG、RHBG、SHROOM3、UTR N、HLA-DRB1、OR6C68 和 XIRP2。我们的结果可能为高危 NBL 的发病机制和临床过程中相关基因和信号通路提供新信息。
