MPC-6 Clinical significance of whole chromosomal aberration signatures in non-metastatic medulloblastomas treated with 18Gy of craniospinal irradiation

Background: One of the most significant challenges is a reduction in the dose of craniospinal irradiation (CSI) in patients with medulloblastoma to minimize neurological sequelae. However, a North American clinical trial failed to show the prognostic non-inferiority of lower-dose irradiation compared to that associated with standard-dose radiation therapy for non-metastatic medulloblastomas. A European retrospective study revealed that whole chromosomal aberration signatures (WCASs) are a potential prognostic factor in Group 3/4 medulloblastoma without metastasis, but whether the molecular signature has the same clinical impact in patients treated with lower-dose CSI remains unknown. Methods: We conducted DNA methylation analysis using an Illumina Infinium Human Methylation EPIC BeadChip array to investigate molecular prognostic markers in 23 medulloblastoma patients who were registered in the Japan Pediatric Molecular Neuro-Oncology Group and treated with lower-dose CSI relative to standard treatment. A WCAS was defined as the presence of at least two of three chromosomal changes as follows: chromosome (chr) 7 gain, chr 8 loss, and chr 11 gain.Results: All patients presented with no residue or a residual tumor smaller than 1.5 cm2 after surgery without metastasis. The median age at onset was 6.9 years, and the median follow-up period was 80.6 months. CSI was delivered at a median dose of 18.0 Gy. Regarding molecular subgrouping, there were 5 WNT, 2 SHH, 1 Group 3, and 15 Group 4 medulloblastomas. Seven patients with Group 3/4 medulloblastomas showed WCASs and had significantly better prognosis than those without the alteration (5-year progression-free survival 100% vs. 63%, p = 0.046). Two late relapses occurred at 89 and 115 months after diagnosis, respectively, and one of these patients presented with a WCAS.Conclusion: WCAS may be a molecular prognostic marker not only in patients with medulloblastoma treated with standard-dose CSI but also in those treated with lower-dose irradiation.