晶能客戶在Hepatology上發(fā)表腫瘤研究新成果

瀏覽次數(shù)：3162　發(fā)布日期：2014-8-14　來(lái)源：本站　本站原創(chuàng)，轉(zhuǎn)載請(qǐng)注明出處

來(lái)自上海交通大學(xué)、復(fù)旦大學(xué)和第二軍醫(yī)大學(xué)的研究人員，采用外顯子組測(cè)序方法揭示出了肝母細(xì)胞瘤（hepatoblastoma）的一些新突變和癌基因，并證實(shí)它們與Wnt信號(hào)通路以及泛素連接酶復(fù)合體相關(guān)。這一研究發(fā)現(xiàn)已在國(guó)際著名肝臟疾病雜志Hepatology（最新影響因子12.003）在線發(fā)表。

上海交通大學(xué)的何祥火(Xianghuo He)教授、復(fù)旦大學(xué)的董巋然（Kuiran Dong）教授以及第二軍醫(yī)大學(xué)的王紅陽(yáng)（Hongyang Wang）院士是這篇論文的共同通訊作者。

為了鑒別出肝母細(xì)胞瘤的新突變，研究人員對(duì)6對(duì)肝母細(xì)胞瘤及匹配淋巴細(xì)胞進(jìn)行了全外顯子組測(cè)序。由此鑒別出了21個(gè)基因上的24種體細(xì)胞非同義突變，其中大多數(shù)的為新發(fā)突變，包括Wnt信號(hào)通路中CTNNB1 (G512V)和CAPRIN2 (R968H/S969C)基因的三個(gè)新突變。還發(fā)現(xiàn)了從前證實(shí)與泛素連接酶復(fù)合體相關(guān)的一些基因：SPOP、KLHL22、TRPC4AP和RNF169。

研究人員證實(shí)，在功能上CTNNB1 (G512V)和CAPRIN2 (R968H/S969C)均為功能獲得性突變，在肝母細(xì)胞瘤中CAPRIN2 (R968H/S969C)激活了Wnt信號(hào)通路。這些研究結(jié)果表明在肝母細(xì)胞瘤中存在Wnt信號(hào)通路激活，通過(guò)在42個(gè)肝母細(xì)胞瘤腫瘤中對(duì)β-catenin進(jìn)行免疫組化染色進(jìn)一步證實(shí)了這一點(diǎn)。

隨后，他們利用shRNA介導(dǎo)RNA干擾，評(píng)估了21種突變基因?qū)τ诟文讣?xì)胞瘤細(xì)胞生存的影響。研究結(jié)果表明1種新的癌基因CAPRIN2和3種抑癌基因SPOP、OR5I1及CDC20B影響了肝母細(xì)胞瘤的細(xì)胞生長(zhǎng)。并且，研究人員發(fā)現(xiàn)在肝母細(xì)胞瘤細(xì)胞中SPOP S119N是一種功能喪失性突變。他們最終證實(shí)SPOP可通過(guò)調(diào)控CDKN2B表達(dá)抑制肝母細(xì)胞瘤的細(xì)胞增殖。這些研究結(jié)果擴(kuò)展了肝母細(xì)胞瘤的遺傳變異圖譜，闡明了Wnt和泛素信號(hào)通路調(diào)控異常在肝母細(xì)胞瘤的腫瘤形成中起著重要的作用。

外顯子組測(cè)序（Exome sequencing）是近年發(fā)展起來(lái)的一種利用序列捕獲技術(shù)將全基因組外顯子區(qū)域DNA捕捉并富集后進(jìn)行高通量測(cè)序的基因組分析方法。是一種選擇基因組的編碼序列的高效策略，相對(duì)于基因組測(cè)序其成本較低。目前，外顯子組測(cè)序已經(jīng)在米勒綜合癥、歌舞伎綜合癥、重型顱腦畸形等孟德?tīng)柤膊〉难芯恐械玫匠晒?yīng)用。還有其它一些癌癥和復(fù)雜性疾病也應(yīng)用外顯子組測(cè)序觀察到高度相關(guān)的突變。

文章中外顯子測(cè)序、SNP芯片以及后續(xù)的大部分?jǐn)?shù)據(jù)分析均由晶能生物完成。

晶能生物推薦原文摘要：
Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex

Abstract：

Hepatoblastoma (HB) is the most common primary liver tumor in children. Mutations in the β-catenin gene that leads to constitutive activation of Wnt pathway have been detected in a large proportion of HB tumors. To identify novel mutations in HB, we performed whole-exome sequencing of 6 paired HB tumors and their corresponding lymphocytes. This identified 24 somatic non-synonymous mutations in 21 genes, many of which were novel, including three novel mutations targeting the CTNNB1 (G512V) and CAPRIN2 (R968H/S969C) genes in the Wnt pathway, and genes previously shown to be involved in the ubiquitin ligase complex (SPOP,KLHL22, TRPC4AP and RNF169). Functionally, both the CTNNB1 (G512V) and CAPRIN2 (R968H/S969C) were observed to be gain-of-functional mutations, and theCAPRIN2 (R968H/S969C) was also shown to activate the Wnt pathway in HB cells. These findings suggested the activation of the Wnt pathway in HB, which was confirmed by immunohistochemical staining of the β-catenin in 42 HB tumors. We further used shRNA-mediated interference to assess the effect of 21 mutated genes on HB cell survival. The results suggested that 1 novel oncogene (CAPRIN2) and 3 tumor suppressors (SPOP, OR5I1 and CDC20B) influence HB cell growth. Moreover, we found that SPOP S119N is a loss-of-function mutation in HB cells. We finally demonstrated that one of the mechanisms by which SPOP inhibits HB cell proliferation is through regulating CDKN2B expression. Conclusion: these results extend the landscape of genetic alterations in HB and highlight the dysregulation of Wnt and ubiquitin pathways in HB tumorigenesis. (Hepatology 2014;)

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晶能客戶在Hepatology上發(fā)表腫瘤研究新成果