儿童外周神经母细胞源性肿瘤的CNV及其临床病理学意义

发布时间：2018-05-24 11:05

  本文选题：外周神经母细胞源性肿瘤 + Oncoscan　； 参考：《首都医科大学》2017年硕士论文

【摘要】：目的探讨儿童外周神经母细胞源性肿瘤(peripheral neuroblastic tumors,pNTs)的全基因组拷贝数改变(Copy Number Variation,CNV)及9个常见肿瘤相关基因的突变,并分析这些改变的临床病理学意义。材料与方法收集24例pNTs福尔马林固定、石蜡包埋组织标本及其患者临床病理学信息,其中包括16例神经母细胞瘤(Neuroblastoma,NB)及8例节细胞神经母细胞瘤(Ganglioneuroblastoma,GNB)。运用全基因组扫描技术(Oncoscan),结合Oncoscan Nexus软件,检测并分析全基因组拷贝数改变(Copy Number Variation,CNV)【包括普通杂合性缺失(Loss of Heterozygosity,LOH)和拷贝数中性杂合性缺失(Copy Neutral LOH,CNLOH)】及9个常见肿瘤相关基因(BRAF,EGFR,IDH1,IDH2,KRAS,NRAS,PIK3CA,PTEN,TP53)突变。同时,探讨CNV及突变与临床病理学指标(性别、年龄、临床分期、危险度分级及MYCN基因扩增)的相关性。结果24例pNTs组织中,所有染色体都存在一个或一个以上CNV,且获得远远多于缺失,其中7号染色体及17号染色体获得频率较高,分别为62.5%(15/24)及87.50%(21/24),并且17q获得更易发生于高危组病例中(P=0.007)。除了18号及Y染色体外,其余22条染色体都存在LOH,其中发生频率较高的前五位为1号、3号、11号、16号及X染色体,分别为50%(12/24)、66.67%(16/24)、37.50%(9/24)、95.83%(23/24)及54.17%(13/24)。而且,NB的总CNV明显多于GNB(P=0.000)。染色体CNV区段的基因所涉及的主要信号转导通路有染色质修饰(83.33%,20/24),RAS通路(79.17%,19/24),细胞周期/凋亡通路(75%,18/24),基因组稳定(75%,18/24),NOTCH通路(66.67%,16/24),TGF-β通路(66.67%,16/24),HH通路(66.67%,16/24),APC通路(58.33%,14/24),转录调控通路(54.17%,13/24)及PI3K通路(50%,12/24)。另外,在24例pNTs患儿中,6例(25%,6/24)存在CNLOH,所涉及染色体或染色体区段为5号、9号、16号、19号及3p、12q、15q,并且此6例患儿均为NB。我们的实验结果还显示,24例pNTs中,9例(37.5%,9/24)存在TP53突变,7例(29.17%,7/24)存在NRAS突变,7例(29.17%,7/24)存在EGFR突变,3例(12.5%,3/24)存在KRAS突变,1例(4.17%,1/24)存在PTEN突变,1例(4.17%,1/24)存在PIK3CA突变。24例pNTs均不存在BRAF、IDH1及IDH2的突变。发生频率最高的TP53突变与pNTs患者的年龄、性别、临床分期、危险度分级及生存时间无明显相关性。结论Oncoscan能够非常好地应用于福尔马林固定、石蜡包埋组织,且一次性可完成全基因组CNV及9个肿瘤相关基因突变的检测,同时可定位CNV区域所涉及的肿瘤相关基因。pNTs是存在多种分子遗传学变化的肿瘤。CNV特别是拷贝数获得是pNTs的重要遗传学变化,CNLOH可能是NB的独特变化。少数CNV具有一定临床病理学意义。关于CNV区域所涉及基因及相关信号转导通路在pNTs中的意义尚需进一步研究。
[Abstract]:Objective to investigate the genomic copy number changes of peripheral neuroblastic tumors in children and the mutations of nine common tumor-associated genes, and to analyze the clinicopathological significance of these changes. Materials and methods the clinicopathological information of 24 cases of pNTs formalin fixed and paraffin embedded tissues were collected, including 16 cases of neuroblastoma neb and 8 cases of ganglioneuroblastoma1. The whole genome scanning technique was used to combine with Oncoscan Nexus software. To detect and analyze the copy Number variation of the whole genome (including loss of heterozygosity and copy number neutral heterozygosity loss) and nine common tumor-associated genes, BRAFFIDH1IDH2KRASNASNRASPIK3CACANTENTP53, and to detect and analyze the mutations of copy Number variation (Number) and nine common tumor-associated genes (BRAFIDH1IDH2KRASNASNRASIK3CAPTENTENTP53). At the same time, the relationship between CNV and mutation and clinicopathological indexes (sex, age, clinical stage, risk grade and MYCN gene amplification) was investigated. Results in 24 cases of pNTs, all the chromosomes had one or more CNVs, and the frequencies of chromosome 7 and chromosome 17 were higher than those of deletion. It was 62.5 / 24) and 87.50 / 21 / 24, respectively, and 17q was more likely to occur in high risk group cases. With the exception of chromosome 18 and chromosome Y, the other 22 chromosomes had LOHs, and the top five chromosomes with higher frequency were chromosome 1, chromosome 3, chromosome 11, chromosome 16 and chromosome X, which were 50 / 12 / 24 / 66.67 / 66.67 / 66.67 / 66.50 / 37.50 / 95.83 / 23 / 24) and 54.1713 / 24 / 24 respectively. Moreover, the total CNV of NB was significantly higher than that of GNB P0. 000. 鏌撹壊浣揅NV鍖烘�电殑鍩哄洜鎵�娑夊強鐨勪富瑕佷俊鍙疯浆瀵奸，

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