Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.

中文翻译：

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松果体母细胞瘤分为具有不同临床病理特征的分子亚组：罕见脑肿瘤联盟注册研究。

松果体母细胞瘤 (PBs) 是一种罕见的侵袭性小儿松果体脑肿瘤，尽管进行了强化治疗，但总体存活率适中。我们试图定义 PB 的临床和分子谱，为这种孤儿癌症提供新的治疗方法。从罕见脑肿瘤联盟的 29 个中心收集了 91 例 PB 或幕上原始神经外胚层肿瘤 (sPNETs/CNS-PNETs) 和 2 例中分化松果体实质肿瘤 (PPTIDs) 的肿瘤、血液和临床数据。我们使用全局 DNA 甲基化分析从 72/93 例中定义了 PB 的核心组，将其划分为五个分子亚组。拷贝数、全外显子组和靶向测序以及miRNA表达分析用于评估每个亚组的临床病理意义。被指定为第 1 组和第 2 组的肿瘤几乎完全在第 1 组和第 2 组肿瘤中分别表现出 62% 和 100% 的 miRNA 生物发生基因（DICER1、DROSHA 和 DGCR8）的有害纯合功能丧失改变。分别在 RB 和 MYC 亚组中观察到致癌 MYC-miR-17/92-RB1 通路的反复改变，其特征是 RB1 丢失伴随 miR-17/92 的增加，以及 MYC 的反复增加或扩增。PB 亚组表现出不同的临床特征：组 1-3 出现在年龄较大的儿童中（中位年龄 5.2-14.0 岁）并且具有中等至极好的生存率（5 年 OS 为 68.0-100%），而组 RB 和 MYC PB 患者更年轻（中位年龄 1.3-1.4 岁），生存率低（5 年 OS 分别为 37.5% 和 28.6%）。我们确定了诊断时年龄 < 3 岁、转移性疾病、省略前期辐射和 chr 16q 损失作为所有 PB 的重要负面预后因素。我们的研究结果表明，PB 与亚组相关的临床表型和存活率表现出显着的分子异质性。除了揭示新的生物学和治疗方法外，PB 的分子亚群还​​可用于降低具有有利生物学肿瘤的患者的治疗强度。