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

Abstract

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.

Experience of like-SJMB03 protocolin treatment of children with medulloblastomain the age group over 3 years:results of an intercenter pilot study

“…В свою очередь, неблагоприятными прогностическими факторами являются: субтотальное или частичное удаление первичного очага опухолевого поражения, наличие метастатического поражения, крупноклеточного-анапластического гистологического варианта опухоли; наличие в опухолевых клетках амплификации гена С-MYC, амплификации гена N-MYC, мутации в гене TP53. Прогностическая значимость наличия в опухолевых клетках Iso17q требует дополнительного изучения [6][7][8][9][10][11][12][13][14][15][16][17].…”

“…В контексте указанных выше исследований изучение редукции дозы краниоспинального облучения (КСО) для пациентов в группе высокого риска не проводилось. Суммарная очаговая доза (СОД) локального этапа определялась в соответствии с протоколом и типом фракционирования (54-59,4 Гр при конвенциональном фракционировании, 68 Гр -при режиме гиперфракционирования) [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17].…”