Application of Genome-Wide DNA Methylation Analysis to Differentiate a Case of Radiation-Induced Glioblastoma From Late-Relapsed Medulloblastoma

Hiraki, Takamasa; Fukuoka, Kohei; Mori, Makiko; Arakawa, Yuki; Matsushita, Yuko; Hibiya, Yuko; Honda, Sunao; Kobayashi, Masao; Tanami, Yutaka; Ichimura, Koichi; Hirato, Junko; Kurihara, Jun; Nakazawa, Atsuko; Koh, Katsuyoshi

doi:10.1093/jnen/nlab043

Cited by 5 publications

(4 citation statements)

References 13 publications

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“…It is known that some group 4 tumors recur very late, that is, after 5 years from onset. In our cohort, there were two late recurrences and one of them was subtype VII, which was not included in the poor prognostic subtype [ 16 ]. This very late recurrent case indicates a limitation of the novel subtyping; thus, efforts to enable much better risk stratification to improve the prognosis and quality of life of patients with medulloblastoma should continue.…”

Section: Discussionmentioning

confidence: 99%

Subtyping of Group 3/4 medulloblastoma as a potential prognostic biomarker among patients treated with reduced dose of craniospinal irradiation: a Japanese Pediatric Molecular Neuro-Oncology Group study

Fukuoka,

Kurihara,

Shofuda

et al. 2023

acta neuropathol commun

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Background One of the most significant challenges in patients with medulloblastoma is reducing the dose of craniospinal irradiation (CSI) to minimize neurological sequelae in survivors. Molecular characterization of patients receiving lower than standard dose of CSI therapy is important to facilitate further reduction of treatment burden. Methods We conducted DNA methylation analysis using an Illumina Methylation EPIC array to investigate molecular prognostic markers in 38 patients with medulloblastoma who were registered in the Japan Pediatric Molecular Neuro-Oncology Group and treated with reduced-dose CSI. Results Among the patients, 23 were classified as having a standard-risk and 15 as high-risk according to the classic classification based on tumor resection rate and presence of metastasis, respectively. The median follow-up period was 71.5 months (12.0–231.0). The median CSI dose was 18 Gy (15.0–24.0) in both groups, and 5 patients in the high-risk group received a CSI dose of 18.0 Gy. Molecular subgrouping revealed that the standard-risk cohort included 5 WNT, 2 SHH, and 16 Group 3/4 cases; all 15 patients in the high-risk cohort had Group 3/4 medulloblastoma. Among the patients with Group 3/4 medulloblastoma, 9 of the 31 Group 3/4 cases were subclassified as subclass II, III, and V, which were known to an association with poor prognosis according to the novel subtyping among the subgroups. Patients with poor prognostic subtype showed worse prognosis than that of others (5-year progression survival rate 90.4% vs. 22.2%; p < 0.0001). The result was replicated in the multivariate analysis (hazard ratio12.77, 95% confidence interval for hazard ratio 2.38–99.21, p value 0.0026 for progression-free survival, hazard ratio 5.02, 95% confidence interval for hazard ratio 1.03–29.11, p value 0.044 for overall survival). Conclusion Although these findings require validation in a larger cohort, the present findings suggest that novel subtyping of Group 3/4 medulloblastoma may be a promising prognostic biomarker even among patients treated with lower-dose CSI than standard treatment.

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Section: Discussionmentioning

confidence: 99%

Subtyping of Group 3/4 medulloblastoma as a potential prognostic biomarker among patients treated with reduced dose of craniospinal irradiation: a Japanese Pediatric Molecular Neuro-Oncology Group study

Fukuoka,

Kurihara,

Shofuda

et al. 2023

acta neuropathol commun

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“…This cohort was included because it is now known that primary tumor recurrences this late after diagnosis are very rare, and many of these tumors may actually be RIGs that were either never biopsied or pathologically misclassified. 20,21 This cohort was further divided into non-glioma (2a; n=139) and glioma (2b; n=157) as first malignancy to allow for distinction in the case that some of the Cohort 2b patients may have had a rare late recurrence rather than a RIG.…”

Section: Study Design and Data Collectionmentioning

confidence: 99%

Population-based analysis of radiation-induced gliomas after cranial radiotherapy for childhood cancers

Leary

Anderson-Mellies

Green

2022

Preprint

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Background: Cranial radiotherapy (RT) is used to treat pediatric central nervous system (CNS) cancers and leukemias. RT carries a risk of secondary CNS malignancies, including radiation-induced gliomas, the epidemiology of which is poorly understood. Methods: This retrospective study using SEER registry data (1975-2016) included two cohorts. Cohort 1 included patients diagnosed with Grade III/IV or ungraded glioma as a second malignancy at least 2 years after receiving beam radiation and/or chemotherapy for a first malignancy diagnosed at ages 0-19 years, either a primary CNS tumor treated with RT (1a, n=57) or leukemia with unknown RT treatment (1b, n=20). Cohort 2 included patients with possible missed RIG who received RT for a primary CNS tumor diagnosed at 0-19 and then died of presumed progressive disease more than 5 years after diagnosis, since previous studies have documented many missed RIGs in this group (n=296). Controls (n=10,687) included all other patients ages 0-19 who received RT for a first CNS tumor or leukemia who did not fit inclusion criteria above. Results: For Cohort 1 (likely/definite RIGs), 0.97% of patients receiving cranial RT went on to develop RIG. 3.39% of patients receiving cranial RT for primary CNS tumors fell in Cohort 2 (potential RIGs). Median latency to RIG diagnosis was 11.1 years; latency was significantly shorter for Cohort 1b (median 10.0, range 5.0-16.1) vs. 1a (12.0, 3.6-34.4, p=0.018). Median OS for Cohort 1 was 9.0 months. Receiving surgery, radiation, or chemotherapy were all associated with a non-statistically significant improvement in OS (p 0.1-0.2). 1.8% of brain tumor deaths in the cohort fell in Cohort 1, with an additional 7.9% in Cohort 2. Conclusion: Within the limitations of a population-based study, 1-4% of patients undergoing cranial RT for pediatric cancers later develop RIG, which is incurable and can occur anywhere from 3-35 years later. 2-10% of pediatric brain tumor deaths are attributable to RIG. Effective treatment of RIG remains unclear and is thus deserving of increased attention in preclinical and clinical studies.

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“…Thus, the optimal therapeutic approach for RIGs is not well defined [ 5 ]. Moreover, few studies investigated genetic alterations in RIGs [ 9 – 15 ], and their clinical impact remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Assessment of therapeutic outcome and role of reirradiation in patients with radiation-induced glioma

Ohno

Miyakita²,

Takahashi³

et al. 2022

Radiat Oncol

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Background We sought to clarify the optimal follow-up, therapeutic strategy, especially the role of reirradiation, and the diagnostic impact of isocitrate dehydrogenase (IDH) 1 and 2 mutation status in patients with radiation-induced glioma (RIG). Methods We retrospectively reviewed the clinical characteristics and treatment outcomes of 11 patients with high-grade glioma who satisfied Cahan’s criteria for RIG in our database during 2001–2021. IDH 1/2 mutations were analyzed by Sanger sequencing and/or pyrosequencing. Results The RIGs included glioblastoma with IDH 1/2 wild-type (n = 7), glioblastoma not otherwise specified (n = 2), anaplastic astrocytoma with IDH1/2 wild-type (n = 1), and anaplastic astrocytoma not otherwise specified (n = 1). The median period from primary disease and RIG diagnosis was 17 years (range: 9–30 years). All patients underwent tumor removal or biopsy, 5 patients postoperatively received reirradiation combined with chemotherapy, and 6 patients were treated with chemotherapy alone. The median progression-free and survival times were 11.3 and 28.3 months. The median progression-free survival time of patients treated with reirradiation and chemotherapy (n = 5) tended to be longer than that of patients that received chemotherapy alone (n = 6) (17.0 vs 8.1 months). However, the median survival time was similar (29.6 vs 27.4 months). Local recurrence was observed in 5 patients treated with chemotherapy alone, whereas in 2 patients among 4 patients treated with reirradiation and chemotherapy. None of the patients developed radiation necrosis. In one case, the primary tumor was diffuse astrocytoma with IDH2 mutant, and the secondary tumor was glioblastoma with IDH 1/2 wild-type. Based on the difference of IDH2 mutation status, the secondary tumor with IDH 1/2 wild-type was diagnosed as a de novo tumor that was related to the previous radiation therapy. Conclusions RIG can occur beyond 20 years after successfully treating the primary disease using radiotherapy; thus, cancer survivors should be informed of the long-term risk of developing RIG and the need for timely neuroimaging evaluation. Reirradiation combined with chemotherapy appears to be feasible and has favorable outcomes. Determining the IDH1/2 mutational status is useful to establish RIG diagnosis when the primary tumor is glioma.

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Application of Genome-Wide DNA Methylation Analysis to Differentiate a Case of Radiation-Induced Glioblastoma From Late-Relapsed Medulloblastoma

Cited by 5 publications

References 13 publications

Subtyping of Group 3/4 medulloblastoma as a potential prognostic biomarker among patients treated with reduced dose of craniospinal irradiation: a Japanese Pediatric Molecular Neuro-Oncology Group study

Subtyping of Group 3/4 medulloblastoma as a potential prognostic biomarker among patients treated with reduced dose of craniospinal irradiation: a Japanese Pediatric Molecular Neuro-Oncology Group study

Population-based analysis of radiation-induced gliomas after cranial radiotherapy for childhood cancers

Assessment of therapeutic outcome and role of reirradiation in patients with radiation-induced glioma

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