Title |
Medulloblastoma therapy generates risk of a poorly-prognostic H3 wild-type subgroup of diffuse intrinsic pontine glioma: a report from the International DIPG Registry
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Published in |
Acta Neuropathologica Communications, July 2018
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DOI | 10.1186/s40478-018-0570-9 |
Pubmed ID | |
Authors |
Hunter C. Gits, Maia Anderson, Stefanie Stallard, Drew Pratt, Becky Zon, Christopher Howell, Chandan Kumar-Sinha, Pankaj Vats, Katayoon Kasaian, Daniel Polan, Martha Matuszak, Daniel E. Spratt, Marcia Leonard, Tingting Qin, Lili Zhao, James Leach, Brooklyn Chaney, Nancy Yanez Escorza, Jacob Hendershot, Blaise Jones, Christine Fuller, Sarah Leary, Ute Bartels, Eric Bouffet, Torunn I. Yock, Patricia Robertson, Rajen Mody, Sriram Venneti, Arul M. Chinnaiyan, Maryam Fouladi, Nicholas G. Gottardo, Carl Koschmann |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United Kingdom | 1 | 10% |
United States | 1 | 10% |
Spain | 1 | 10% |
Canada | 1 | 10% |
Australia | 1 | 10% |
Unknown | 5 | 50% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 8 | 80% |
Practitioners (doctors, other healthcare professionals) | 1 | 10% |
Scientists | 1 | 10% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 42 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 5 | 12% |
Student > Master | 5 | 12% |
Student > Bachelor | 5 | 12% |
Student > Doctoral Student | 2 | 5% |
Student > Ph. D. Student | 2 | 5% |
Other | 6 | 14% |
Unknown | 17 | 40% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 13 | 31% |
Biochemistry, Genetics and Molecular Biology | 4 | 10% |
Agricultural and Biological Sciences | 3 | 7% |
Neuroscience | 2 | 5% |
Chemical Engineering | 1 | 2% |
Other | 1 | 2% |
Unknown | 18 | 43% |