Medulloblastoma is an aggressive primitive neuroectodermal tumor of the cerebellum that is more common in children than in adults. In the past decade, advances in understanding the molecular drivers of medulloblastoma have identified four molecular subgroups defined by experimental gene expression profiles: the WNT pathway, sonic hedgehog (SHH) pathway, and subgroups 3 and 4 (non-SHH/WNT). Medulloblastoma of adults belong primarily to the SHH category. Vismodegib, an SHH-pathway inhibitor, FDA-approved in 2012 for treatment of basal cell carcinoma, has been used successfully in the setting of chemorefractory medulloblastoma, but not as a first-line therapy. In 2016, we reported a case of an adult patient with a sustained response of an unresectable multifocal form of adult medulloblastoma to vismodegib. Molecular analysis in that case revealed mutations in TP53 and a cytogenetic abnormality, i17q, that is prevalent and most often associated with subgroup 4 rather than the SHH-activated form of medulloblastoma. Here, we report further whole-genome analysis of that patient (designated Patient A) as well as an additional adult patient (Patient B) whose tumor harbored the SHH molecular subgroup but which was unresponsive to visgmodegib therapy. Comparison of these disparate responses highlights the challenges to tailoring SHH-targeted treatment in individual patients with adult medulloblastoma.

中文翻译：

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表达SHH的成年成年髓样母细胞瘤对声波刺猬抑制剂vismodegib的差异反应：全基因组分析。

髓母细胞瘤是小脑的侵袭性原始神经外胚层肿瘤，在儿童中比在成年人中更常见。在过去的十年中，在了解髓母细胞瘤的分子驱动因素方面的进展已经确定了由实验基因表达谱定义的四个分子亚组：WNT途径，声波刺猬（SHH）途径以及3和4亚组（非SHH / WNT）。成人的髓母细胞瘤主要属于SHH类别。Vismodegib是一种SHH途径抑制剂，2012年获得FDA批准用于治疗基底细胞癌，已成功用于化学难治性髓母细胞瘤的治疗，但未作为一线治疗。2016年，我们报告了一例成年人患者，该患者对不可切除的多灶性成年髓母细胞瘤对维莫昔单抗的持续反应。在那种情况下，分子分析揭示了TP53突变和细胞遗传异常，即i17q，这种现象很普遍，最常与亚组4相关，而不是由SHH激活的髓母细胞瘤形式。在这里，我们报告了对该患者（指定为患者A）以及其肿瘤带有SHH分子亚组但对visgmodegib治疗无反应的另一位成年患者（指定为B患者）的全基因组分析。这些不同反应的比较突出显示了在成年髓母细胞瘤个体患者中定制SHH靶向治疗的挑战。我们报告了对该患者（指定为患者A）以及另一名成年患者（患者B）的全基因组分析，该患者的肿瘤带有SHH分子亚组，但对visgmodegib治疗无反应。这些不同反应的比较凸显了成年成年髓母细胞瘤患者适应SHH靶向治疗的挑战。我们报告了对该患者（指定为患者A）以及另一名成年患者（患者B）的全基因组分析，该患者的肿瘤带有SHH分子亚组，但对visgmodegib治疗无反应。这些不同反应的比较突出显示了在成年髓母细胞瘤个体患者中定制SHH靶向治疗的挑战。