Oncogene mutation profiling of pediatric solid tumors reveals significant subsets of embryonal rhabdomyosarcoma and neuroblastoma with mutated genes in growth signaling pathways.
Oncogene mutation profiling of pediatric solid tumors reveals significant subsets of embryonal rhabdomyosarcoma and neuroblastoma with mutated genes in growth signaling pathways.
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DOI：
10.1158/1078-0432.ccr-11-2056
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发表时间：
2012-02-01
期刊：
影响因子：
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通讯作者：
Ladanyi M
中科院分区：
文献类型：
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作者：
Shukla N;Ameur N;Yilmaz I;Nafa K;Lau CY;Marchetti A;Borsu L;Barr FG;Ladanyi M
与成人癌症中癌基因突变的众多广泛筛查相比，在儿科实体瘤中进行的筛查很少。为了确定儿科癌症中的新突变和潜在治疗靶点，我们在几种主要儿科实体癌的大集合中进行了基于高通量测序的分析，包括神经母细胞瘤（NB），尤文肉瘤（ES），横纹肌肉瘤（RMS）和促结缔组织增生性小圆细胞瘤（DSRCT）。我们设计了一种高度多重的基于Sequenom的检测方法，以询问29个基因中的275个复发突变。从192个NB、75个ES、89个RMS和24个DSRCT样品中提取基因组DNA。通过桑格测序验证所有突变。在13%的NB样本、4%的ES样本、21.1%的RMS样本和无DSRCT样本中鉴定出突变。10.4%的NB样本中存在ALK突变。其余NB突变涉及BRAF、RAS和MAP 2K 1基因，在携带ALK突变的样本中不存在。突变在胚胎型RMS（ERMS）样本中（28.3%）比肺泡型RMS（ARMS）（3.5%）更常见。除了先前发现的RAS和FGFR 4突变，我们首次报告了PIK 3CA和CTNNB 1（β-连环蛋白）突变，分别占ERMS的4.9%和3.3%。在ERMS、ES和NB中，我们发现了几种被认为是其他癌症驱动因素的癌基因突变的新发生。总体而言，NB和ERMS包含生长信号传导途径中具有非重叠突变基因的病例的重要子集。肿瘤分析可以将儿科实体瘤患者的一个子集确定为激酶抑制剂或RAS靶向治疗的候选者。
Compared to the numerous broad screens for oncogene mutations in adult cancers, very few have been performed in pediatric solid tumors. To identify novel mutations and potential therapeutic targets in pediatric cancers, we performed a high-throughput Sequenom-based analysis in large sets of several major pediatric solid cancers, including neuroblastoma (NB), Ewing sarcoma (ES), rhabdomyosarcoma (RMS), and desmoplastic small round cell tumor (DSRCT). We designed a highly multiplexed Sequenom-based assay to interrogate 275 recurrent mutations across 29 genes. Genomic DNA was extracted from 192 NB, 75 ES, 89 RMS, and 24 DSRCT samples. All mutations were verified by Sanger sequencing. Mutations were identified in 13% of NB samples, 4% of ES samples, 21.1% of RMS samples, and no DSRCT samples. ALK mutations were present in 10.4% of NB samples. The remainder of NB mutations involved the BRAF, RAS, and MAP2K1 genes and were absent in samples harboring ALK mutations. Mutations were more common in embryonal RMS (ERMS) samples (28.3%) than alveolar RMS (ARMS) (3.5%). In addition to previously identified RAS and FGFR4 mutations, we report for the first time PIK3CA and CTNNB1 (Beta-Catenin) mutations in 4.9% and 3.3% of ERMS, respectively. In ERMS, ES, and NB, we identified novel occurrences of several oncogene mutations recognized as drivers in other cancers. Overall, NB and ERMS contain significant subsets of cases with non-overlapping mutated genes in growth signaling pathways. Tumor profiling can identify a subset of pediatric solid tumor patients as candidates for kinase inhibitors or RAS-targeted therapies.