發(fā)布時間：2018-05-24 11:05

  本文選題：外周神經(jīng)母細胞源性腫瘤 + Oncoscan��； 參考：《首都醫(yī)科大學》2017年碩士論文

【摘要】：目的探討兒童外周神經(jīng)母細胞源性腫瘤(peripheral neuroblastic tumors,pNTs)的全基因組拷貝數(shù)改變(Copy Number Variation,CNV)及9個常見腫瘤相關(guān)基因的突變,并分析這些改變的臨床病理學意義。材料與方法收集24例pNTs福爾馬林固定、石蠟包埋組織標本及其患者臨床病理學信息,其中包括16例神經(jīng)母細胞瘤(Neuroblastoma,NB)及8例節(jié)細胞神經(jīng)母細胞瘤(Ganglioneuroblastoma,GNB)。運用全基因組掃描技術(shù)(Oncoscan),結(jié)合Oncoscan Nexus軟件,檢測并分析全基因組拷貝數(shù)改變(Copy Number Variation,CNV)【包括普通雜合性缺失(Loss of Heterozygosity,LOH)和拷貝數(shù)中性雜合性缺失(Copy Neutral LOH,CNLOH)】及9個常見腫瘤相關(guān)基因(BRAF,EGFR,IDH1,IDH2,KRAS,NRAS,PIK3CA,PTEN,TP53)突變。同時,探討CNV及突變與臨床病理學指標(性別、年齡、臨床分期、危險度分級及MYCN基因擴增)的相關(guān)性。結(jié)果24例pNTs組織中,所有染色體都存在一個或一個以上CNV,且獲得遠遠多于缺失,其中7號染色體及17號染色體獲得頻率較高,分別為62.5%(15/24)及87.50%(21/24),并且17q獲得更易發(fā)生于高危組病例中(P=0.007)。除了18號及Y染色體外,其余22條染色體都存在LOH,其中發(fā)生頻率較高的前五位為1號、3號、11號、16號及X染色體,分別為50%(12/24)、66.67%(16/24)、37.50%(9/24)、95.83%(23/24)及54.17%(13/24)。而且,NB的總CNV明顯多于GNB(P=0.000)。染色體CNV區(qū)段的基因所涉及的主要信號轉(zhuǎn)導通路有染色質(zhì)修飾(83.33%,20/24),RAS通路(79.17%,19/24),細胞周期/凋亡通路(75%,18/24),基因組穩(wěn)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),轉(zhuǎn)錄調(diào)控通路(54.17%,13/24)及PI3K通路(50%,12/24)。另外,在24例pNTs患兒中,6例(25%,6/24)存在CNLOH,所涉及染色體或染色體區(qū)段為5號、9號、16號、19號及3p、12q、15q,并且此6例患兒均為NB。我們的實驗結(jié)果還顯示,24例pNTs中,9例(37.5%,9/24)存在TP53突變,7例(29.17%,7/24)存在NRAS突變,7例(29.17%,7/24)存在EGFR突變,3例(12.5%,3/24)存在KRAS突變,1例(4.17%,1/24)存在PTEN突變,1例(4.17%,1/24)存在PIK3CA突變。24例pNTs均不存在BRAF、IDH1及IDH2的突變。發(fā)生頻率最高的TP53突變與pNTs患者的年齡、性別、臨床分期、危險度分級及生存時間無明顯相關(guān)性。結(jié)論Oncoscan能夠非常好地應用于福爾馬林固定、石蠟包埋組織,且一次性可完成全基因組CNV及9個腫瘤相關(guān)基因突變的檢測,同時可定位CNV區(qū)域所涉及的腫瘤相關(guān)基因。pNTs是存在多種分子遺傳學變化的腫瘤。CNV特別是拷貝數(shù)獲得是pNTs的重要遺傳學變化,CNLOH可能是NB的獨特變化。少數(shù)CNV具有一定臨床病理學意義。關(guān)于CNV區(qū)域所涉及基因及相關(guān)信號轉(zhuǎn)導通路在pNTs中的意義尚需進一步研究。
[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鐨勫熀鍥犳墍娑夊強鐨勪富瑕佷俊鍙瘋漿瀵奸，

本文編號：1928820