Pineoblastoma is a rare embryonal tumor of childhood that is conventionally treated with high-dose craniospinal irradiation (CSI). Multi-dimensional molecular evaluation of pineoblastoma and associated intertumoral heterogeneity is lacking. Herein, we report outcomes and molecular features of children with pineoblastoma from two multi-center, risk-adapted trials (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. The clinical cohort consisted of 58 patients with histologically diagnosed pineoblastoma (SJMB03 = 30, SJYC07 = 12, non-protocol = 16, including 12 managed with SJMB03-like therapy). The SJMB03 protocol comprised risk-adapted CSI (average-risk = 23.4 Gy, high-risk = 36 Gy) with radiation boost to the primary site and adjuvant chemotherapy. The SJYC07 protocol consisted of induction chemotherapy, consolidation with focal radiation (intermediate-risk) or chemotherapy (high-risk), and metronomic maintenance therapy. The molecular cohort comprised 43 pineal parenchymal tumors profiled by DNA methylation array (n = 43), whole-exome sequencing (n = 26), and RNA-sequencing (n = 16). Respective 5-year progression-free survival rates for patients with average-risk or high-risk disease on SJMB03 or SJMB03-like therapy were 100% and 56.5 ± 10.3% (P = 0.007); respective 2-year progression-free survival rates for those with intermediate-risk or high-risk disease on SJYC07 were 14.3 ± 13.2% and 0% (P = 0.375). Of patients with average-risk disease treated with SJMB03/SJMB03-like therapy, 17/18 survived without progression. DNA-methylation analysis revealed four clinically relevant pineoblastoma subgroups: PB-A, PB-B, PB-B-like, and PB-FOXR2. Pineoblastoma subgroups differed in age at diagnosis, propensity for metastasis, cytogenetics, and clinical outcomes. Alterations in the miRNA-processing pathway genes DICER1, DROSHA, and DGCR8 were recurrent and mutually exclusive in PB-B and PB-B-like subgroups; PB-FOXR2 samples universally overexpressed the FOXR2 proto-oncogene. Our findings suggest superior outcome amongst older children with average-risk pineoblastoma treated with reduced-dose CSI. The identification of biologically and clinically distinct pineoblastoma subgroups warrants consideration of future molecularly-driven treatment protocols for this rare pediatric brain tumor entity.

中文翻译：

---

松果体母细胞瘤的风险适应治疗和生物异质性：前瞻性、多中心 SJMB03 和 SJYC07 试验的综合临床病理分析。


松果体母细胞瘤是一种罕见的儿童胚胎肿瘤，通常采用高剂量颅脊髓照射（CSI）进行治疗。缺乏对松果体母细胞瘤和相关肿瘤间异质性的多维分子评估。在此，我们报告了两项多中心、风险适应试验（SJMB03 适用于≥ 3 岁患者；SJYC07 适用于 < 3 岁患者）的结果和分子特征，并由非方案机构队列进行补充。临床队列由 58 名经组织学诊断的松果体母细胞瘤患者组成（SJMB03 = 30，SJYC07 = 12，非方案 = 16，其中 12 名接受 SJMB03 类治疗）。 SJMB03 方案包括风险适应 CSI（平均风险 = 23.4 Gy，高风险 = 36 Gy）以及对原发部位的放射加强和辅助化疗。 SJYC07方案包括诱导化疗、局部放疗（中危）或化疗（高危）巩固治疗以及节拍维持治疗。该分子队列包括 43 个松果体实质肿瘤，通过 DNA 甲基化阵列（n = 43）、全外显子组测序（n = 26）和 RNA 测序（n = 16）进行分析。使用SJMB03或SJMB03类药物治疗的平均风险或高风险疾病患者的5年无进展生存率分别为100%和56.5±10.3%（P = 0.007）； SJYC07 治疗中危或高危疾病患者的 2 年无进展生存率分别为 14.3 ± 13.2% 和 0%（P = 0.375）。在接受 SJMB03/SJMB03 类疗法治疗的平均风险疾病患者中，17/18 的患者存活且未出现进展。 DNA 甲基化分析揭示了四个临床相关的松果体母细胞瘤亚组：PB-A、PB-B、PB-B 样和 PB-FOXR2。 松果体母细胞瘤亚组在诊断年龄、转移倾向、细胞遗传学和临床结果方面存在差异。 miRNA 加工途径基因 DICER1、DROSHA 和 DGCR8 的改变在 PB-B 和 PB-B 样亚组中反复出现且相互排斥； PB-FOXR2 样本普遍过表达 FOXR2 原癌基因。我们的研究结果表明，接受减量 CSI 治疗的平均风险松果体母细胞瘤年龄较大儿童的预后较好。生物学和临床上不同的松果体母细胞瘤亚组的鉴定值得考虑未来针对这种罕见的儿科脑肿瘤实体的分子驱动治疗方案。