目的:髓母细胞瘤是儿童最常见的恶性脑肿瘤,是儿童癌症相关死亡的主要原因。最近的转录研究表明,髓母细胞瘤包含至少四个分子亚群,每个人都有不同的人口统计数据,遗传学,和临床结果。髓母细胞瘤亚型分型已成为亚组特异性治疗的关键。使用基因表达测定来确定临床标本的分子亚组是该儿科癌症的分子生物学期待已久的应用。
方法:在目前的研究中,我们建立了一个髓母细胞瘤转录组数据库,该数据库包含从三个已发表的数据集(GSE21140,GSE37382和GSE37418)中检索的460个样本.有了这个数据库,我们确定了一个与髓母细胞瘤亚组显著相关的23个基因特征,分类准确率达到95.2%.
结果:在142例中国髓母细胞瘤患者的长期队列中进一步验证了23个基因特征。23个基因签名将21例患者分类为WNT(15%),41为SHH(29%),16为第3组(11%),第4组64人(45%)。对于WNT患者,SHH,第3组和第4组5年总生存率达到80%,62%,27%,47%,分别(p<0.0001),同时5年无进展生存率达到80%,52%,27%,45%,分别(p<0.0001)。此外,与SHH/TP53野生型肿瘤和其他亚组相比,SHH/TP53突变型肿瘤的预后较差。我们证明,通过23个基因签名和Northcott的NanoString分析进行的亚组分配具有高度可比性,一致率为96.4%。
结论:结论:我们提出了一种新的基因标签,能够准确可靠地将FFPE髓母细胞瘤样品分配到其分子亚群,可作为临床髓母细胞瘤亚型分型的辅助工具。将来有必要将该基因标签纳入前瞻性临床试验以进一步评估其临床。
OBJECTIVE: Medulloblastoma is the most common childhood malignant brain tumor and is a leading cause of cancer-related death in children. Recent transcriptional studies have shown that medulloblastomas comprise at least four molecular subgroups, each with distinct demographics, genetics, and clinical outcomes. Medulloblastoma subtyping has become critical for subgroup-specific therapies. The use of gene expression assays to determine the molecular subgroup of clinical specimens is a long-awaited application of molecular biology for this pediatric cancer.
METHODS: In the current study, we established a medulloblastoma transcriptome database of 460 samples retrieved from three published datasets (GSE21140, GSE37382, and GSE37418). With this database, we identified a 23-gene signature that is significantly associated with the medulloblastoma subgroups and achieved a classification accuracy of 95.2%.
RESULTS: The 23-gene signature was further validated in a long-term cohort of 142 Chinese medulloblastoma patients. The 23-gene signature classified 21 patients as WNT (15%), 41 as SHH (29%), 16 as Group 3 (11%), and 64 as Group 4 (45%). For patients of WNT, SHH, Group 3, and Group 4, 5-year overall-survival rate reached 80%, 62%, 27%, and 47%, respectively (p < 0.0001), meanwhile 5-year progression-free survival reached 80%, 52%, 27%, and 45%, respectively (p < 0.0001). Besides, SHH/TP53-mutant tumors were associated with worse prognosis compared with SHH/TP53 wild-type tumors and other subgroups. We demonstrated that subgroup assignments by the 23-gene signature and Northcott\'s NanoString assay were highly comparable with a concordance rate of 96.4%.
CONCLUSIONS: In conclusion, we present a novel gene signature that is capable of accurately and reliably assigning FFPE medulloblastoma samples to their molecular subgroup, which may serve as an auxiliary tool for medulloblastoma subtyping in the clinic. Future incorporation of this gene signature into prospective clinical trials is warranted to further evaluate its clinical.