Genomic Profiling of a Large Set of Diverse Pediatric Cancers Identifies Known and Novel Mutations across Tumor Spectra.
Genomic Profiling of a Large Set of Diverse Pediatric Cancers Identifies Known and Novel Mutations across Tumor Spectra.
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DOI：
10.1158/0008-5472.can-16-1106
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发表时间：
2017-01-15
期刊：
影响因子：
11.2
通讯作者：
Lipson D
中科院分区：
文献类型：
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作者：
Chmielecki J;Bailey M;He J;Elvin J;Vergilio JA;Ramkissoon S;Suh J;Frampton GM;Sun JX;Morley S;Spritz D;Ali S;Gay L;Erlich RL;Ross JS;Buxhaku J;Davies H;Faso V;Germain A;Glanville B;Miller VA;Stephens PJ;Janeway KA;Maris JM;Meshinchi S;Pugh TJ;Shern JF;Lipson D
儿童癌症的特征通常是低突变负荷和很少的复发突变基因。最近的研究表明，基因组改变可能有助于指导治疗决策和临床试验选择。在这里，我们描述了来自1,215个儿科肿瘤的基因组图谱，这些肿瘤包括肉瘤、颅外胚胎性肿瘤、脑肿瘤、血液恶性肿瘤、癌和性腺肿瘤。可比较的已发表数据集确定了临床相关改变的相似频率，验证了该数据集的生物学相关性。我们在神经母细胞瘤（BEND 5-ALK）和星形细胞瘤（PPP 1CB-ALK）中发现了新型ALK融合，在星形细胞瘤（BCAS 1-BRAF）和神经节胶质瘤（TMEM 106 B-BRAF）中发现了新型BRAF融合，在横纹肌肉瘤中发现了新型PAX 3-GLI 2融合。在非预期恶性肿瘤中观察到先前表征的ALK、NTRK 1和PAX 3融合，挑战了“疾病特异性”改变范例。最后，我们确定了MLL 3和PRSS 1中预测具有功能影响的未知意义的复发性变体。这1，215个肿瘤的数据已公开供发现和验证。
Pediatric cancers are generally characterized by low mutational burden and few recurrently mutated genes. Recent studies suggest that genomic alterations may help guide treatment decisions and clinical trial selection. Here, we describe genomic profiles from 1,215 pediatric tumors representing sarcomas, extracranial embryonal tumors, brain tumors, hematologic malignancies, carcinomas, and gonadal tumors. Comparable published datasets identified similar frequencies of clinically relevant alterations, validating this dataset as biologically relevant. We identified novel ALK fusions in a neuroblastoma (BEND5–ALK) and an astrocytoma (PPP1CB–ALK), novel BRAF fusions in an astrocytoma (BCAS1–BRAF) and a ganglioglioma (TMEM106B–BRAF), and a novel PAX3–GLI2 fusion in a rhabdomyosarcoma. Previously characterized ALK, NTRK1, and PAX3 fusions were observed in unexpected malignancies, challenging the “disease-specific” alterations paradigm. Finally, we identified recurrent variants of unknown significance in MLL3 and PRSS1 predicted to have functional impact. Data from these 1,215 tumors are publicly available for discovery and validation.