Department of Pathology MS# 250, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Acta Neuropathol. 2011 Mar;121(3):381-96. doi: 10.1007/s00401-011-0800-8. Epub 2011 Jan 26.
Medulloblastoma is heterogeneous, being characterized by molecular subgroups that demonstrate distinct gene expression profiles. Activation of the WNT or SHH signaling pathway characterizes two of these molecular subgroups, the former associated with low-risk disease and the latter potentially targeted by novel SHH pathway inhibitors. This manuscript reports the validation of a novel diagnostic immunohistochemical method to distinguish SHH, WNT, and non-SHH/WNT tumors and details their associations with clinical, pathological and cytogenetic variables. A cohort (n = 235) of medulloblastomas from patients aged 0.4-52 years was studied for expression of four immunohistochemical markers: GAB1, β-catenin, filamin A, and YAP1. Immunoreactivity (IR) for GAB1 characterizes only SHH tumors and nuclear IR for β-catenin only WNT tumors. IRs for filamin A and YAP1 identify SHH and WNT tumors. SHH, WNT, and non-SHH/WNT tumors contributed 31, 14, and 55% to the series. All desmoplastic/nodular (D/N) medulloblastomas were SHH tumors, while most WNT tumors (94%) had a classic phenotype. Monosomy 6 was strongly associated with WNT tumors, while PTCH1 loss occurred almost exclusively among SHH tumors. MYC or MYCN amplification and chromosome 17 imbalance occurred predominantly among non-SHH/WNT tumors. Among patients aged 3-16 years and entered onto the SIOP PNET3 trial, outcome was significantly better for children with WNT tumors, when compared to SHH or non-SHH/WNT tumors, which showed similar survival curves. However, high-risk factors (M+ disease, LC/A pathology, MYC amplification) significantly influenced survival in both SHH and non-SHH/WNT groups. We describe a robust method for detecting SHH, WNT, and non-SHH/WNT molecular subgroups in formalin-fixed medulloblastoma samples. In corroborating other studies that indicate the value of combining clinical, pathological, and molecular variables in therapeutic stratification schemes for medulloblastoma, we also provide the first outcome data based on a clinical trial cohort and novel data on how molecular subgroups are distributed across the range of disease.
髓母细胞瘤具有异质性，其特征是存在具有不同基因表达谱的分子亚群。WNT 或 SHH 信号通路的激活是其中两个分子亚群的特征，前者与低风险疾病相关，后者可能成为新型 SHH 通路抑制剂的作用靶点。本文报告了一种新的诊断免疫组织化学方法的验证，该方法可用于区分 SHH、WNT 和非 SHH/WNT 肿瘤，并详细描述了它们与临床、病理和细胞遗传学变量的关系。对来自 0.4-52 岁患者的 235 例髓母细胞瘤队列进行了四种免疫组织化学标志物：GAB1、β-catenin、肌动蛋白 A 和 YAP1 的表达研究。GAB1 的免疫反应性 (IR) 仅特征性地存在于 SHH 肿瘤中，而核 β-catenin 的 IR 仅存在于 WNT 肿瘤中。IRs 用于 filamin A 和 YAP1 可识别 SHH 和 WNT 肿瘤。SHH、WNT 和非 SHH/WNT 肿瘤分别占该系列的 31%、14%和 55%。所有促结缔组织增生性/结节性（D/N）髓母细胞瘤均为 SHH 肿瘤，而大多数 WNT 肿瘤（94%）具有经典表型。单体 6 与 WNT 肿瘤强烈相关，而 PTCH1 缺失几乎仅发生在 SHH 肿瘤中。MYC 或 MYCN 扩增和 17 号染色体不平衡主要发生在非 SHH/WNT 肿瘤中。在年龄为 3-16 岁并参加 SIOP PNET3 试验的患者中，与 SHH 或非 SHH/WNT 肿瘤相比，WNT 肿瘤患儿的预后明显更好，SHH 和非 SHH/WNT 肿瘤的生存曲线相似。然而，高危因素（M+疾病、LC/A 病理、MYC 扩增）显著影响 SHH 和非 SHH/WNT 两组的生存。我们描述了一种在福尔马林固定的髓母细胞瘤样本中检测 SHH、WNT 和非 SHH/WNT 分子亚群的可靠方法。在证实其他研究表明在髓母细胞瘤的治疗分层方案中结合临床、病理和分子变量的价值的同时，我们还提供了首个基于临床试验队列的结果数据以及关于分子亚群在疾病范围内分布的新数据。
