【佳學(xué)基因檢測(cè)】印跡基因 Grb10 的單等位基因缺失促進(jìn)輻照 Nf1+/- 小鼠的腫瘤形成

基因檢測(cè)全套費(fèi)用需要多少錢(qián)比較分析

數(shù)據(jù)分析腫瘤基因檢測(cè)位點(diǎn)的全面性與正確性《腫瘤個(gè)性治療的方法與措施》《PLoS Genet》在?2015 May 22;11(5):e1005235發(fā)表了一篇題目為《印跡基因 Grb10 的單等位基因缺失促進(jìn)輻照 Nf1+/- 小鼠的腫瘤形成》腫瘤靶向藥物治療基因檢測(cè)臨床研究文章。該研究由Rana Mroue,?Brian Huang,?Steve Braunstein,?Ari J Firestone,?Jean L Nakamura?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：

0

腫瘤靶向治療基因檢測(cè)臨床應(yīng)用結(jié)果

印記基因僅從一個(gè)親本等位基因表達(dá)，涉及表達(dá)的等位基因的雜合缺失足以產(chǎn)生蛋白質(zhì)表達(dá)的有效喪失?；蚋淖?cè)谀[瘤發(fā)生中很常見(jiàn)，但印跡基因在這一過(guò)程中的作用尚不清楚。在早期的工作中，我們對(duì)神經(jīng)纖維瘤病 I 腫瘤抑制基因 (NF1) 雜合子小鼠進(jìn)行了誘變，以模擬在受輻射的 NF1 患者中出現(xiàn)的與放療相關(guān)的第二種惡性腫瘤。從我們的小鼠模型建立的腫瘤細(xì)胞系的表達(dá)分析確定 Grb10 表達(dá)廣泛缺失。 Grb10 是一種印跡基因，對(duì)細(xì)胞系和原發(fā)性腫瘤的多態(tài)性分析表明，在我們的小鼠模型中出現(xiàn)的各種 Nf1 突變腫瘤中，表達(dá)的等位基因通常會(huì)丟失。我們進(jìn)行了功能研究以測(cè)試 Grb10 的恢復(fù)或丟失是否會(huì)改變腫瘤生長(zhǎng)的基本特征。在 Nf1 突變腫瘤中恢復(fù) Grb10 會(huì)減少增殖，減少軟瓊脂菌落形成并下調(diào) Ras 信號(hào)傳導(dǎo)。相反，未轉(zhuǎn)化的小鼠胚胎成纖維細(xì)胞中的 Grb10 沉默顯著增加了細(xì)胞增殖并增加了 Ras-GTP 水平。組成型激活的 MEK 的表達(dá)從 Grb10 介導(dǎo)的集落形成減少中拯救了腫瘤細(xì)胞。這些研究表明，Grb10 丟失可能發(fā)生在體內(nèi)腫瘤發(fā)生過(guò)程中，在未轉(zhuǎn)化的原代細(xì)胞中具有功能性后果。在腫瘤中，Grb10 缺失獨(dú)立地促進(jìn) Ras 通路過(guò)度激活，從而促進(jìn)過(guò)度增殖，這是腫瘤發(fā)展的早期特征。在穩(wěn)健的 Nf1 突變小鼠癌癥模型的背景下，這項(xiàng)工作確定了印跡基因在腫瘤發(fā)生中的新作用。

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

Imprinted genes are expressed from only one parental allele and heterozygous loss involving the expressed allele is sufficient to produce complete loss of protein expression. Genetic alterations are common in tumorigenesis but the role of imprinted genes in this process is not well understood. In earlier work we mutagenized mice heterozygous for the Neurofibromatosis I tumor suppressor gene (NF1) to model radiotherapy-associated second malignant neoplasms that arise in irradiated NF1 patients. Expression analysis of tumor cell lines established from our mouse models identified Grb10 expression as widely absent. Grb10 is an imprinted gene and polymorphism analysis of cell lines and primary tumors demonstrates that the expressed allele is commonly lost in diverse Nf1 mutant tumors arising in our mouse models. We performed functional studies to test whether Grb10 restoration or loss alter fundamental features of the tumor growth. Restoring Grb10 in Nf1 mutant tumors decreases proliferation, decreases soft agar colony formation and downregulates Ras signaling. Conversely, Grb10 silencing in untransformed mouse embryo fibroblasts significantly increased cell proliferation and increased Ras-GTP levels. Expression of a constitutively activated MEK rescued tumor cells from Grb10-mediated reduction in colony formation. These studies reveal that Grb10 loss can occur during in vivo tumorigenesis, with a functional consequence in untransformed primary cells. In tumors, Grb10 loss independently promotes Ras pathway hyperactivation, which promotes hyperproliferation, an early feature of tumor development. In the context of a robust Nf1 mutant mouse model of cancer this work identifies a novel role for an imprinted gene in tumorigenesis.