通过对 HIT2000 和 I-HIT-MED 队列进行改良的临床-分子分层，鉴定非 WNT/非 SHH 型髓母细胞瘤的低危和高危极高危患者。
Identification of low and very high-risk patients with non-WNT/non-SHH medulloblastoma by improved clinico-molecular stratification of the HIT2000 and I-HIT-MED cohorts.
机构信息
Department for Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
出版信息
Acta Neuropathol. 2023 Jan;145(1):97-112. doi: 10.1007/s00401-022-02522-4. Epub 2022 Dec 2.
Molecular groups of medulloblastoma (MB) are well established. Novel risk stratification parameters include Group 3/4 (non-WNT/non-SHH) methylation subgroups I-VIII or whole-chromosomal aberration (WCA) phenotypes. This study investigates the integration of clinical and molecular parameters to improve risk stratification of non-WNT/non-SHH MB. Non-WNT/non-SHH MB from the HIT2000 study and the HIT-MED registries were selected based on availability of DNA-methylation profiling data. MYC or MYCN amplification and WCA of chromosomes 7, 8, and 11 were inferred from methylation array-based copy number profiles. In total, 403 non-WNT/non-SHH MB were identified, 346/403 (86%) had a methylation class family Group 3/4 methylation score (classifier v11b6) ≥ 0.9, and 294/346 (73%) were included in the risk stratification modeling based on Group 3 or 4 score (v11b6) ≥ 0.8 and subgroup I-VIII score (mb_g34) ≥ 0.8. Group 3 MB (5y-PFS, survival estimation ± standard deviation: 41.4 ± 4.6%; 5y-OS: 48.8 ± 5.0%) showed poorer survival compared to Group 4 (5y-PFS: 68.2 ± 3.7%; 5y-OS: 84.8 ± 2.8%). Subgroups II (5y-PFS: 27.6 ± 8.2%) and III (5y-PFS: 37.5 ± 7.9%) showed the poorest and subgroup VI (5y-PFS: 76.6 ± 7.9%), VII (5y-PFS: 75.9 ± 7.2%), and VIII (5y-PFS: 66.6 ± 5.8%) the best survival. Multivariate analysis revealed subgroup in combination with WCA phenotype to best predict risk of progression and death. The integration of clinical (age, M and R status) and molecular (MYC/N, subgroup, WCA phenotype) variables identified a low-risk stratum with a 5y-PFS of 94 ± 5.7 and a very high-risk stratum with a 5y-PFS of 29 ± 6.1%. Validation in an international MB cohort confirmed the combined stratification scheme with 82.1 ± 6.0% 5y-PFS in the low and 47.5 ± 4.1% in very high-risk groups, and outperformed the clinical model. These newly identified clinico-molecular low-risk and very high-risk strata, accounting for 6%, and 21% of non-WNT/non-SHH MB patients, respectively, may improve future treatment stratification.
髓母细胞瘤（MB）的分子群已得到很好的确立。新的风险分层参数包括 3/4 组（非 WNT/非 SHH）甲基化亚组 I-VIII 或全染色体异常（WCA）表型。本研究旨在探讨整合临床和分子参数以改善非 WNT/非 SHH MB 的风险分层。根据 DNA 甲基化分析数据的可用性，从 HIT2000 研究和 HIT-MED 注册处选择非 WNT/非 SHH MB。通过基于甲基化阵列的拷贝数分析推断 MYC 或 MYCN 扩增和 7、8 和 11 号染色体的 WCA。总共鉴定出 403 例非 WNT/非 SHH MB，346/403（86%）的甲基化分类家族 3/4 甲基化评分（分类器 v11b6）≥0.9，并且 294/346（73%）根据 3 组或 4 组评分（v11b6）≥0.8 和亚组 I-VIII 评分（mb_g34）≥0.8 纳入风险分层建模。3 组 MB（5y-PFS，生存估计±标准差：41.4±4.6%；5y-OS：48.8±5.0%）与 4 组（5y-PFS：68.2±3.7%；5y-OS：84.8±2.8%）相比，生存情况较差。亚组 II（5y-PFS：27.6±8.2%）和 III（5y-PFS：37.5±7.9%）的预后最差，而亚组 VI（5y-PFS：76.6±7.9%）、VII（5y-PFS：75.9±7.2%）和 VIII（5y-PFS：66.6±5.8%）的预后最好。多变量分析显示，亚组与 WCA 表型结合可最佳预测进展和死亡的风险。临床（年龄、M 和 R 状态）和分子（MYC/N、亚组、WCA 表型）变量的整合确定了一个低风险分层，其 5y-PFS 为 94±5.7%，而高风险分层为 5y-PFS 为 29±6.1%。在国际 MB 队列中的验证证实了联合分层方案，低风险组的 5y-PFS 为 82.1±6.0%，高风险组的 5y-PFS 为 47.5±4.1%，优于临床模型。这些新确定的临床分子低风险和高风险分层分别占非 WNT/非 SHH MB 患者的 6%和 21%，可能改善未来的治疗分层。
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