Department of Pediatrics, Division of Pediatric Hematology-Oncology; Michigan Medicine, Ann Arbor, MI, 48109, USA.
Department of Pathology, Michigan Medicine, Ann Arbor, MI, 48109, USA.
Acta Neuropathol Commun. 2018 Jul 26;6(1):67. doi: 10.1186/s40478-018-0570-9.
With improved survivorship in medulloblastoma, there has been an increasing incidence of late complications. To date, no studies have specifically addressed the risk of radiation-associated diffuse intrinsic pontine glioma (DIPG) in medulloblastoma survivors. Query of the International DIPG Registry identified six cases of DIPG with a history of medulloblastoma treated with radiotherapy. All patients underwent central radiologic review that confirmed a diagnosis of DIPG. Six additional cases were identified in reports from recent cooperative group medulloblastoma trials (total n = 12; ages 7 to 21 years). From these cases, molecular subgrouping of primary medulloblastomas with available tissue (n = 5) revealed only non-WNT, non-SHH subgroups (group 3 or 4). The estimated cumulative incidence of DIPG after post-treatment medulloblastoma ranged from 0.3-3.9%. Posterior fossa radiation exposure (including brainstem) was greater than 53.0 Gy in all cases with available details. Tumor/germline exome sequencing of three radiation-associated DIPGs revealed an H3 wild-type status and mutational signature distinct from primary DIPG with evidence of radiation-induced DNA damage. Mutations identified in the radiation-associated DIPGs had significant molecular overlap with recurrent drivers of adult glioblastoma (e.g. NRAS, EGFR, and PTEN), as opposed to epigenetic dysregulation in H3-driven primary DIPGs. Patients with radiation-associated DIPG had a significantly worse median overall survival (median 8 months; range 4-17 months) compared to patients with primary DIPG. Here, it is demonstrated that DIPG occurs as a not infrequent complication of radiation therapy in survivors of pediatric medulloblastoma and that radiation-associated DIPGs may present as a poorly-prognostic distinct molecular subgroup of H3 wild-type DIPG. Given the abysmal survival of these cases, these findings provide a compelling argument for efforts to reduce exposure of the brainstem in the treatment of medulloblastoma. Additionally, patients with radiation-associated DIPG may benefit from future therapies targeted to the molecular features of adult glioblastoma rather than primary DIPG.
随着髓母细胞瘤存活率的提高，其晚期并发症的发生率也在不断增加。迄今为止，尚无研究专门针对接受放疗的髓母细胞瘤幸存者中与放疗相关的弥漫性内在脑桥神经胶质瘤（DIPG）的风险。对国际 DIPG 登记处的查询发现了 6 例有髓母细胞瘤病史并接受放疗的 DIPG 病例。所有患者均接受了中枢影像学复查，以确认 DIPG 的诊断。在最近的协作组髓母细胞瘤试验的报告中又发现了 6 例（共 12 例；年龄 7 至 21 岁）。从这些病例中，对有组织学标本的原发性髓母细胞瘤进行了分子亚组分析（n=5），结果仅发现非 WNT、非 SHH 亚组（3 或 4 组）。治疗后髓母细胞瘤的 DIPG 累积发生率为 0.3-3.9%。所有有详细资料的病例中，后颅窝放疗剂量（包括脑干）均大于 53.0Gy。对 3 例与放疗相关的 DIPG 肿瘤/种系外显子测序显示 H3 野生型状态和突变特征与原发性 DIPG 不同，有放射诱导的 DNA 损伤证据。在与放疗相关的 DIPG 中发现的突变与成人胶质母细胞瘤的常见驱动因素（如 NRAS、EGFR 和 PTEN）有显著的分子重叠，而不是 H3 驱动的原发性 DIPG 中的表观遗传失调。与原发性 DIPG 患者相比，与放疗相关的 DIPG 患者的中位总生存期明显更差（中位 8 个月；范围 4-17 个月）。本研究表明，DIPG 是儿童髓母细胞瘤幸存者放疗后常见的并发症之一，与放疗相关的 DIPG 可能是 H3 野生型 DIPG 预后不良的独特分子亚群。鉴于这些病例的生存率极差，这些发现有力地证明了有必要努力减少脑桥在治疗髓母细胞瘤中的放疗暴露。此外，与放疗相关的 DIPG 患者可能受益于针对成人胶质母细胞瘤而非原发性 DIPG 的分子特征的未来治疗。
