Medulloblastomas (MB) molecularly designated as Group 3 (Grp 3) MB represent a more clinically aggressive tumor variant which, as a group, displays heterogeneous molecular characteristics and disease outcomes. Reliable risk stratification of Grp 3 MB would allow for appropriate assignment of patients to aggressive treatment protocols and, vice versa, for sparing adverse effects of high-dose radio-chemotherapy in patients with standard or low-risk tumors. Here we performed RNA-based analysis on an international cohort of 179 molecularly designated Grp 3 MB treated with HIT protocols. We analyzed the clinical significance of differentially expressed genes, thereby developing optimal prognostic subdivision of this MB molecular group. We compared the transcriptome profiles of two Grp 3 MB subsets with various outcomes (76 died within the first 60 months vs. 103 survived this period) and identified 224 differentially expressed genes (DEG) between these two clinical groups (Limma R algorithm, adjusted p-value < 0.05). We selected the top six DEG overexpressed in the unfavorable cohort for further survival analysis and found that expression of all six genes strongly correlated with poor outcomes. However, only high expression of KIRREL2 was identified as an independent molecular prognostic indicator of poor patients’ survival. Based on clinical and molecular patterns, four risk categories were outlined for Grp 3 MB patients: i. low-risk: M0-1/MYC non-amplified/KIRREL2 low (n = 48; 5-year OS—95%); ii. standard-risk: M0-1/MYC non-amplified/KIRREL2 high or M2-3/MYC non-amplified/KIRREL2 low (n = 65; 5-year OS—70%); iii. high-risk: M2-3/MYC non-amplified/KIRREL2 high (n = 36; 5-year OS—30%); iv. very high risk—all MYC amplified tumors (n = 30; 5-year OS—0%). Cross-validated survival models incorporating KIRREL2 expression with clinical features allowed for the reclassification of up to 50% of Grp 3 MB patients into a more appropriate risk category. Finally, KIRREL2 immunopositivity was also identified as a predictive indicator of Grp 3 MB poor survival, thus suggesting its application as a possible prognostic marker in routine clinical settings. Our results indicate that integration of KIRREL2 expression in risk stratification models may improve Grp 3 MB outcome prediction. Therefore, simple gene and/or protein expression analyses for this molecular marker could be easily adopted for Grp 3 MB prognostication and may help in assigning patients to optimal therapeutic approaches in prospective clinical trials.

成神经管细胞瘤 (MB) 在分子上被指定为第 3 组 (Grp 3) MB 代表一种更具临床侵袭性的肿瘤变体，作为一个群体，它显示出异质的分子特征和疾病结果。Grp 3 MB 的可靠风险分层将允许将患者适当分配到积极的治疗方案，反之亦然，以减少标准或低风险肿瘤患者高剂量放化疗的副作用。在这里，我们对使用 HIT 方案处理的 179 名分子指定的 Grp 3 MB 国际队列进行了基于 RNA 的分析。我们分析了差异表达基因的临床意义，从而开发了该 MB 分子群的最佳预后细分。p值 < 0.05）。我们选择了不利队列中过度表达的前六个 DEG 进行进一步的生存分析，并发现所有六个基因的表达与不良结果密切相关。然而，只有KIRREL2的高表达被确定为不良患者生存的独立分子预后指标。根据临床和分子模式，为 Grp 3 MB 患者概述了四个风险类别： i. 低风险：M0-1/ MYC非扩增/ KIRREL2低（n  = 48；5 年 OS—95%）；二. 标准风险：M0-1/ MYC非扩增/ KIRREL2高或 M2-3/ MYC非扩增/ KIRREL2低（n = 65; 5 年 OS—70%)；三. 高风险：M2-3/ MYC非扩增/ KIRREL2高（n  = 36；5 年 OS—30%）；四. 非常高的风险——所有MYC扩增的肿瘤（n  = 30；5 年 OS—0%）。将KIRREL2表达与临床特征相结合的交叉验证生存模型允许将多达 50% 的 Grp 3 MB 患者重新分类为更合适的风险类别。最后，KIRREL2 免疫阳性也被确定为 Grp 3 MB 生存率低下的预测指标，因此表明其在常规临床环境中作为可能的预后标志物的应用。我们的结果表明KIRREL2的整合风险分层模型中的表达可能会改善 Grp 3 MB 结果预测。因此，该分子标记的简单基因和/或蛋白质表达分析可以很容易地用于 Grp 3 MB 预后，并可能有助于在前瞻性临床试验中为患者分配最佳治疗方法。