Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, 03080, Republic of Korea.
Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
Acta Neuropathol. 2018 Jun;135(6):939-953. doi: 10.1007/s00401-018-1845-8. Epub 2018 Apr 11.
Despite great advances in understanding of molecular pathogenesis and achievement of a high cure rate in medulloblastoma, recurrent medulloblastomas are still dismal. Additionally, misidentification of secondary malignancies due to histological ambiguity leads to misdiagnosis and eventually to inappropriate treatment. Nevertheless, the genomic characteristics of recurrent medulloblastomas are poorly understood, largely due to a lack of matched primary and recurrent tumor tissues. We performed a genomic analysis of recurrent tumors from 17 pediatric medulloblastoma patients. Whole transcriptome sequencing revealed that a subset of recurrent tumors initially diagnosed as locally recurrent medulloblastomas are secondary glioblastomas after radiotherapy, showing high similarity to the non-G-CIMP proneural subtype of glioblastoma. Further analysis, including whole exome sequencing, revealed missense mutations or complex gene fusion events in PDGFRA with augmented expression in the secondary glioblastomas after radiotherapy, implicating PDGFRA as a putative driver in the development of secondary glioblastomas after treatment exposure. This result provides insight into the possible application of PDGFRA-targeted therapy in these second malignancies. Furthermore, genomic alterations of TP53 including 17p loss or germline/somatic mutations were also found in most of the secondary glioblastomas after radiotherapy, indicating a crucial role of TP53 alteration in the process. On the other hand, analysis of recurrent medulloblastomas revealed that the most prevalent alterations are the loss of 17p region including TP53 and gain of 7q region containing EZH2 which already exist in primary tumors. The 7q gain events are frequently accompanied by high expression levels of EZH2 in both primary and recurrent medulloblastomas, which provides a clue to a new therapeutic target to prevent recurrence. Considering the fact that it is often challenging to differentiate between recurrent medulloblastomas and secondary glioblastomas after radiotherapy, our findings have major clinical implications both for correct diagnosis and for potential therapeutic interventions in these devastating diseases.
尽管在理解分子发病机制方面取得了重大进展，并且髓母细胞瘤的治愈率很高，但复发性髓母细胞瘤的预后仍然较差。此外，由于组织学上的模糊性导致继发性恶性肿瘤的误诊，最终导致治疗不当。然而，复发性髓母细胞瘤的基因组特征了解甚少，主要是因为缺乏匹配的原发和复发性肿瘤组织。我们对 17 名小儿髓母细胞瘤患者的复发性肿瘤进行了基因组分析。全转录组测序显示，一部分最初诊断为局部复发性髓母细胞瘤的复发性肿瘤在放疗后是继发性胶质母细胞瘤，与非 G-CIMP 倾向于神经型胶质母细胞瘤高度相似。进一步的分析，包括全外显子组测序，揭示了在放疗后继发性胶质母细胞瘤中 PDGFRA 的错义突变或复杂基因融合事件，提示 PDGFRA 是治疗后继发性胶质母细胞瘤发展的潜在驱动因素。这一结果为这些第二恶性肿瘤中 PDGFRA 靶向治疗的可能应用提供了依据。此外，在放疗后大多数继发性胶质母细胞瘤中还发现了 TP53 的基因组改变，包括 17p 缺失或种系/体细胞突变，表明 TP53 改变在这一过程中起着关键作用。另一方面，对复发性髓母细胞瘤的分析表明，最常见的改变是 17p 区域缺失，包括 TP53，以及 7q 区域增益，其中包含原发性肿瘤中已存在的 EZH2。7q 增益事件常伴有原发性和复发性髓母细胞瘤中 EZH2 的高表达水平，这为预防复发提供了一个新的治疗靶点。鉴于区分放疗后复发性髓母细胞瘤和继发性胶质母细胞瘤往往具有挑战性，我们的发现对这些毁灭性疾病的正确诊断和潜在治疗干预具有重要的临床意义。
