【佳學(xué)基因檢測(cè)】人類(lèi)和鼠類(lèi) NF1 單倍體不足導(dǎo)致細(xì)胞周期和 DNA 修復(fù)途徑擾動(dòng)的證據(jù)

腫瘤基因檢測(cè)龍頭企業(yè)國(guó)產(chǎn)

在高峰論壇中博士醫(yī)師年度雙基練習(xí)體會(huì)到《BMC Genomics》在.?2010 Mar 22;11:194.發(fā)表了一篇題目為《人類(lèi)和鼠類(lèi) NF1 單倍體不足導(dǎo)致細(xì)胞周期和 DNA 修復(fù)途徑擾動(dòng)的證據(jù)》腫瘤靶向藥物治療基因檢測(cè)臨床研究文章。該研究由Alexander Pemov,?Caroline Park,?Karlyne M Reilly,?Douglas R Stewart等完成。促進(jìn)了腫瘤的正確治療與個(gè)性化用藥的發(fā)展，進(jìn)一步強(qiáng)調(diào)了基因信息檢測(cè)與分析的重要性。

腫瘤靶向藥物及正確治療臨床研究?jī)?nèi)容關(guān)鍵詞：

腫瘤靶向治療基因檢測(cè)臨床應(yīng)用結(jié)果

基因解碼基因檢測(cè)的研究介紹：1 型神經(jīng)纖維瘤病 (NF1) 是一種常見(jiàn)的單基因腫瘤易感性疾病，繼發(fā)于腫瘤抑制基因 NF1 的突變。 NF1 的單倍體不足通過(guò)細(xì)胞間信號(hào)傳導(dǎo)的變化促進(jìn)了允許的致瘤環(huán)境，但是這種腫瘤促進(jìn)作用的細(xì)胞內(nèi)機(jī)制尚不清楚。大多數(shù)原代人類(lèi) NF1+/- 細(xì)胞難以獲得，但已從大型 NF1 家族中收集了類(lèi)淋巴母細(xì)胞系 (LCL)?；蚪獯a基因檢測(cè)假設(shè) NF1 單倍體不足的遺傳效應(yīng)可以通過(guò)比較來(lái)自 NF1 受影響和未受影響的個(gè)體的體細(xì)胞、非腫瘤細(xì)胞 (LCL) 中的全基因組轉(zhuǎn)錄譜來(lái)辨別。作為異質(zhì)性的跨物種過(guò)濾器，基因解碼基因檢測(cè)將兩個(gè)人類(lèi)親屬的基因解碼基因檢測(cè)的研究結(jié)果與來(lái)自年齡和性別匹配的 Nf1+/- 和野生型小鼠的脾源性 B 淋巴細(xì)胞的全基因組轉(zhuǎn)錄譜進(jìn)行比較，并使用基因集富集分析 (GSEA)、Onto-Express、Pathway-Express 和 MetaCore 工具來(lái)識(shí)別在 NF1-單倍體不足中受干擾的基因?；蚪獯a基因檢測(cè)的研究結(jié)果：基因解碼基因檢測(cè)觀察到人類(lèi) LCL 中 NF1 和 CD19+ 小鼠 B 淋巴細(xì)胞中 Nf1 的中度表達(dá)。使用 t 檢驗(yàn)評(píng)估單個(gè)轉(zhuǎn)錄本，基因解碼基因檢測(cè)觀察到 NF1-單倍體不足的 LCL 和 Nf1-單倍體不足的小鼠 B 淋巴細(xì)胞中轉(zhuǎn)錄組的適度表達(dá)差異。然而，GSEA、Onto-Express、Pathway-Express 和 MetaCore 分析確定了控制細(xì)胞周期、DNA 復(fù)制和修復(fù)、轉(zhuǎn)錄和翻譯以及免疫反應(yīng)的基因，這些基因在人類(lèi)和小鼠的 NF1 單倍體不足條件下是賊受干擾的?；蚪獯a基因檢測(cè)的研究結(jié)論：當(dāng)基因的一個(gè)等位基因的缺失足以引起疾病時(shí)，就會(huì)出現(xiàn)單倍體不足。單倍體不足傳統(tǒng)上被視為一種被動(dòng)狀態(tài)?；蚪獯a基因檢測(cè)對(duì)擾動(dòng)的、上調(diào)的細(xì)胞周期和 DNA 修復(fù)途徑的觀察可能在功能上導(dǎo)致 NF1 單倍體不足作為一種“活躍狀態(tài)”，賊終促進(jìn)野生型等位基因的喪失。

腫瘤發(fā)生與反復(fù)轉(zhuǎn)移國(guó)際數(shù)據(jù)庫(kù)描述：

Background:?Neurofibromatosis type 1 (NF1) is a common monogenic tumor-predisposition disorder that arises secondary to mutations in the tumor suppressor gene NF1. Haploinsufficiency of NF1 fosters a permissive tumorigenic environment through changes in signalling between cells, however the intracellular mechanisms for this tumor-promoting effect are less clear. Most primary human NF1+/- cells are a challenge to obtain, however lymphoblastoid cell lines (LCLs) have been collected from large NF1 kindreds. We hypothesized that the genetic effects of NF1-haploinsufficiency may be discerned by comparison of genome-wide transcriptional profiling in somatic, non-tumor cells (LCLs) from NF1-affected and -unaffected individuals. As a cross-species filter for heterogeneity, we compared the results from two human kindreds to whole-genome transcriptional profiling in spleen-derived B lymphocytes from age- and gender-matched Nf1+/- and wild-type mice, and used gene set enrichment analysis (GSEA), Onto-Express, Pathway-Express and MetaCore tools to identify genes perturbed in NF1-haploinsufficiency.Results:?We observed moderate expression of NF1 in human LCLs and of Nf1 in CD19+ mouse B lymphocytes. Using the t test to evaluate individual transcripts, we observed modest expression differences in the transcriptome in NF1-haploinsufficient LCLs and Nf1-haploinsuffiicient mouse B lymphocytes. However, GSEA, Onto-Express, Pathway-Express and MetaCore analyses identified genes that control cell cycle, DNA replication and repair, transcription and translation, and immune response as the most perturbed in NF1-haploinsufficient conditions in both human and mouse.Conclusions:?Haploinsufficiency arises when loss of one allele of a gene is sufficient to give rise to disease. Haploinsufficiency has traditionally been viewed as a passive state. Our observations of perturbed, up-regulated cell cycle and DNA repair pathways may functionally contribute to NF1-haploinsufficiency as an "active state" that ultimately promotes the loss of the wild-type allele.