Medulloblastoma therapy generates risk of a poorly-prognostic H3 wild-type subgroup of diffuse intrinsic pontine glioma: a report from the International DIPG Registry

Abstract

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.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0570-9) contains supplementary material, which is available to authorized users.

Comprehensive molecular characterization of pediatric treatment-induced high-grade glioma: A distinct entity despite disparate etiologies with defining molecular characteristics and potential therapeutic targets

“…One TIHGG case in our series clustered with diffuse midline glioma (DMG) but lacked the defining H3K27M mutation (Case 13). One recent case series described three patients who had received prior radiotherapy for medulloblastoma and later developed tumors clinically consistent with DMG 19 . While one case in our series had the H3K27M mutation (Case 7), this case lacked methylation data and was not be able to be clustered against reference cohorts.…”

The role of diffusion tensor imaging metrics in the discrimination between cerebellar medulloblastoma and brainstem glioma

“…Previous literature has shown that medulloblastomas can either originate in the brainstem or directly invade the brainstem, which can cause the misdiagnosis of medulloblastoma as brainstem glioma 1,3,4 . Brainstem lesions have been found in post‐radiotherapy medulloblastoma patients, which can cause uncertainty regarding whether to diagnose the lesions as medulloblastoma recurrence or as new brainstem gliomas 5,6 . These pathologies require different treatment regimens and prognoses.…”

“…These pathologies require different treatment regimens and prognoses. Thus, the differentiation between these two types of tumors is essential for precise therapeutic strategy planning and improved treatment outcomes 1‐6 …”

A Novel Orthotopic Patient-Derived Xenograft Model of Radiation-Induced Glioma Following Medulloblastoma

“…Gliomas can occur as primary brain tumours but may also arise as a consequence of radiation therapy in survivors of other paediatric brain tumours, such as medulloblastoma or ependymoma. Radiation-induced gliomas (RIGs) are at least as, if not more, aggressive than spontaneously occurring gliomas [ 7 , 8 , 9 ], and are invariably fatal, with a cumulative incidence ranging from 0.3% to 3.96% following radiation treatment for paediatric brain tumours [ 8 , 10 ].…”

“…Studies investigating molecular alterations in paediatric RIGs are few and report small numbers of patient samples. These studies suggest that paediatric RIGs demonstrate more overlap with pilocytic astrocytomas (PAs) [ 7 ] and adult primary GBMs [ 8 ] than with paediatric high-grade gliomas. Overexpression of ERBB3, SOX10 and PDGFRA has been reported in paediatric RIG [ 7 , 14 ], as well as mutations in TP53 , PDGFRA and PIK3CA , homozygous deletion of CDKN2A and MTAP , and alterations in multiple receptor tyrosine kinase and Ras-Raf-MAPK genes [ 8 , 14 , 16 , 17 , 18 , 19 , 20 ].…”