未经证实:视网膜母细胞瘤是在幼儿中诊断的恶性眼部肿瘤。大多数视网膜母细胞瘤的遗传特征是RB1基因的双等位基因失活。然而,1.5%的肿瘤显示原癌基因MYCN的高水平扩增。患有MYCN扩增的RB1高的视网膜母细胞瘤的患者在较早的年龄接受诊断,并在临床和组织学上表现出更恶性的表型。这项研究旨在确定将该亚型与其他视网膜母细胞瘤区分开的全基因组分子特征。
未经评估:队列研究。
未经批准:47个视网膜母细胞瘤肿瘤,包含36RB1-/-,4RB1+/-,和7个RB1+/+肿瘤。总的来说,5个视网膜母细胞瘤显示高水平的MYCN扩增,3为RB1+/+,1为RB1+/-,1为RB1-/-。
未经评估:综合分析,基于基因表达,甲基化,和甲基化表达相关性,与其他视网膜母细胞瘤亚型相比,进行了MYCN扩增的RB1高的视网膜母细胞瘤的不同分子成分的鉴定。甲基化和甲基化-表达相关性分析最初在甲基化谱可用的样品子集(n=15)内进行。在整个队列(n=47)和公开数据中交叉验证了显着发现。
未经证实:差异表达基因/途径,差异甲基化基因,和甲基化驱动的差异基因表达。
未经证实:在MYCN扩增的富含RB1的视网膜母细胞瘤中鉴定出大量基因(n=3155)具有不同的表达模式。上调和下调的基因与翻译和细胞周期过程有关,分别。甲基化分析揭示了在MYCN扩增的RB1精通肿瘤中不同的甲基化模式,其中许多对基因表达有显著影响。数据整合鉴定了具有高甲基化状态的40-基因表达特征,导致MYCN扩增的RB1-熟练视网膜母细胞瘤的显著下调。使用整个队列和公共领域表达数据的交叉验证验证了这些基因的总体较低表达,不仅在具有MYCN扩增的RB1熟练背景的视网膜母细胞瘤中,而且在MYCN扩增的神经母细胞瘤中也是如此。这些包括代谢相关的TSTD1基因和细胞周期蛋白依赖性激酶抑制剂基因CDKN2C。
UNASSIGNED:与其他视网膜母细胞瘤相比,MYCN扩增的RB1-proficious视网膜母细胞瘤显示出明显不同的分子特征,包括一组40个高甲基化驱动的下调基因。该基因集可以深入了解MYCN扩增的视网膜母细胞瘤的生物学特性,并可能帮助我们了解更具侵略性的临床行为。
UNASSIGNED: Retinoblastomas are malignant eye tumors diagnosed in young children. Most retinoblastomas are genetically characterized by biallelic inactivation of the RB1 gene. However, 1.5% of tumors demonstrate high-level amplification of the proto-oncogene MYCN. Patients with MYCN-amplified RB1-proficient retinoblastoma receive a diagnosis at an earlier age and show a clinically and histologically more malignant phenotype. This study aimed to identify genome-wide molecular features that distinguish this subtype from other retinoblastomas.
UNASSIGNED: Cohort study.
UNASSIGNED: Forty-seven retinoblastoma tumors, comprising 36 RB1 -/-, 4 RB1 +/-, and 7 RB1 +/+ tumors. In total, 5 retinoblastomas displayed high-level MYCN amplification, with 3 being RB1 +/+, 1 being RB1 +/-, and 1 being RB1 -/- .
UNASSIGNED: Integrated analysis, based on gene expression, methylation, and methylation-expression correlations, was performed to identify distinct molecular components of MYCN-amplified RB1-proficient retinoblastomas compared with other retinoblastoma subtypes. The methylation and methylation-expression correlation analysis was initially conducted within a subset of samples (n = 15) for which methylation profiles were available. The significant findings were cross-validated in the entire cohort (n = 47) and in publicly available data.
UNASSIGNED: Differentially expressed genes/pathways, differentially methylated genes, and methylation-driven differential gene expression.
UNASSIGNED: A large number of genes (n = 3155) were identified with distinct expression patterns in MYCN-amplified RB1-proficient retinoblastomas. The upregulated and downregulated genes were associated with translation and cell-cycle processes, respectively. Methylation analysis revealed distinct methylated patterns in MYCN-amplified RB1-proficient tumors, many of which showing significant impact on gene expression. Data integration identified a 40-gene expression signature with hypermethylated state resulting in a significant downregulation in MYCN-amplified RB1-proficient retinoblastomas. Cross-validation using the entire cohort and the public domain expression data verified the overall lower expression of these genes not only in retinoblastomas with a MYCN-amplified RB1-proficient background, but also in MYCN-amplified neuroblastomas. These include the metabolism-associated TSTD1 gene and the cyclin-dependent kinase inhibitor gene CDKN2C.
UNASSIGNED: MYCN-amplified RB1-proficient retinoblastomas display significantly distinct molecular features compared with other retinoblastomas, including a set of 40 hypermethylation-driven downregulated genes. This gene set can give insight into the biology of MYCN-amplified retinoblastomas and may help us to understand the more aggressive clinical behavior.