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

Acta Neuropathologica Communications

Brooklyn Chaney¹  Lili Zhao¹  Ute Bartels¹  Maia Anderson¹  Drew Pratt¹  Christine Fuller¹  Katayoon Kasaian¹  Christopher Howell¹  Jacob Hendershot¹  Eric Bouffet²  Sarah Leary³  Daniel Polan⁴  Martha Matuszak⁵  Chandan Kumar-Sinha⁵  Daniel E. Spratt⁵  Carl Koschmann⁶  Nicholas G. Gottardo⁷  Becky Zon⁸  Hunter C. Gits⁸  Pankaj Vats⁸  Stefanie Stallard⁸  Blaise Jones⁸  Tingting Qin⁹  James Leach⁹  Nancy Yanez Escorza⁹  Sriram Venneti^1,10  Rajen Mody^1,11  Patricia Robertson^1,11  Maryam Fouladi^1,12  Torunn I. Yock^1,13  Arul M. Chinnaiyan^1,13  Marcia Leonard^1,14 

[1] Michigan Medicine;Department of Biostatistics, University of Michigan School of Public Health;Department of Computational Medicine and Bioinformatics;Department of Haematology and Oncology, Princess Margaret Hospital for Children;Department of Pathology, Michigan Medicine;Department of Pediatrics, Division of Haematology/Oncology, Hospital for Sick Children;Department of Pediatrics, Division of Oncology, Seattle Children’s Hospital;Department of Pediatrics, Division of Pediatric Hematology-Oncology;Department of Radiation Oncology;Division of Biomedical Informatics, Cincinnati Children’s Hospital;Division of Oncology, Cincinnati Children’s Hospital;Division of Pathology, Cincinnati Children’s Hospital;Division of Radiology, Cincinnati Children’s Hospital;Ontario Institute for Cancer Research;

关键词: Secondary malignant neoplasm;    Diffuse intrinsic pontine glioma;    Medulloblastoma;    Cranial irradiation;    Brainstem;   

DOI  :  10.1186/s40478-018-0570-9

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown