Kline Cassie N, Joseph Nancy M, Grenert James P, van Ziffle Jessica, Talevich Eric, Onodera Courtney, Aboian Mariam, Cha Soonmee, Raleigh David R, Braunstein Steve, Torkildson Joseph, Samuel David, Bloomer Michelle, Campomanes Alejandra G de Alba, Banerjee Anuradha, Butowski Nicholas, Raffel Corey, Tihan Tarik, Bollen Andrew W, Phillips Joanna J, Korn W Michael, Yeh Iwei, Bastian Boris C, Gupta Nalin, Mueller Sabine, Perry Arie, Nicolaides Theodore, Solomon David A
Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of California San Francisco (UCSF), San Francisco, California, USA.
Department of Pathology, UCSF, San Francisco, California, USA.
Neuro Oncol. 2017 May 1;19(5):699-709. doi: 10.1093/neuonc/now254.
Molecular profiling is revolutionizing cancer diagnostics and leading to personalized therapeutic approaches. Herein we describe our clinical experience performing targeted sequencing for 31 pediatric neuro-oncology patients.
We sequenced 510 cancer-associated genes from tumor and peripheral blood to identify germline and somatic mutations, structural variants, and copy number changes.
Genomic profiling was performed on 31 patients with tumors including 11 high-grade gliomas, 8 medulloblastomas, 6 low-grade gliomas, 1 embryonal tumor with multilayered rosettes, 1 pineoblastoma, 1 uveal ganglioneuroma, 1 choroid plexus carcinoma, 1 chordoma, and 1 high-grade neuroepithelial tumor. In 25 cases (81%), results impacted patient management by: (i) clarifying diagnosis, (ii) identifying pathogenic germline mutations, or (iii) detecting potentially targetable alterations. The pathologic diagnosis was amended after genomic profiling for 6 patients (19%), including a high-grade glioma to pilocytic astrocytoma, medulloblastoma to pineoblastoma, ependymoma to high-grade glioma, and medulloblastoma to CNS high-grade neuroepithelial tumor with BCOR alteration. Multiple patients had pathogenic germline mutations, many of which were previously unsuspected. Potentially targetable alterations were identified in 19 patients (61%). Additionally, novel likely pathogenic alterations were identified in 3 cases: an in-frame RAF1 fusion in a BRAF wild-type pleomorphic xanthoastrocytoma, an inactivating ASXL1 mutation in a histone H3 wild-type diffuse pontine glioma, and an in-frame deletion within exon 2 of MAP2K1 in a low-grade astrocytic neoplasm.
Our experience demonstrates the significant impact of molecular profiling on diagnosis and treatment of pediatric brain tumors and confirms its feasibility for use at the time of diagnosis or recurrence.
分子谱分析正在彻底改变癌症诊断，并引领个性化治疗方法。在此，我们描述了对31例儿童神经肿瘤患者进行靶向测序的临床经验。
我们对肿瘤和外周血中的510个癌症相关基因进行测序，以识别种系和体细胞突变、结构变异及拷贝数变化。
对31例肿瘤患者进行了基因组谱分析，其中包括11例高级别胶质瘤、8例髓母细胞瘤、6例低级别胶质瘤、1例伴有多层菊形团的胚胎性肿瘤、1例松果体母细胞瘤、1例葡萄膜神经节瘤、1例脉络丛癌、1例脊索瘤和1例高级别神经上皮肿瘤。在25例（81%）病例中，结果通过以下方式影响患者管理：（i）明确诊断，（ii）识别致病种系突变，或（iii）检测潜在可靶向改变。6例（19%）患者在基因组谱分析后病理诊断得到修正，包括将高级别胶质瘤修正为毛细胞型星形细胞瘤、髓母细胞瘤修正为松果体母细胞瘤、室管膜瘤修正为高级别胶质瘤，以及将髓母细胞瘤修正为伴有BCOR改变的中枢神经系统高级别神经上皮肿瘤。多名患者存在致病种系突变，其中许多此前未被怀疑。19例（61%）患者中发现了潜在可靶向改变。此外，在3例病例中发现了新的可能致病改变：BRAF野生型多形性黄色星形细胞瘤中的框内RAF1融合、组蛋白H3野生型弥漫性脑桥胶质瘤中的失活ASXL1突变，以及低级别星形细胞瘤性肿瘤中MAP2K1外显子2内的框内缺失。
我们的经验证明了分子谱分析对儿童脑肿瘤诊断和治疗的重大影响，并证实了其在诊断或复发时使用的可行性。
