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Lancet Oncol述评:MYCN在视网膜母细胞瘤发病中起到重要作用

2013-05-03 Lancet Oncol dxy

原癌基因的发现改变了我们对肿瘤发生机制的认识。之后,对视网膜母细胞瘤基因(RB1)的确定则预示着另一个观念——恶性疾病的发生具有一定遗传基础,即在生殖细胞和体细胞中肿瘤抑制基因的突变会导致肿瘤的形成。事实上,对肿瘤发生的潜伏期进行分析提示,即使在“责任基因”被发现之前,我们也认识到在罹患遗传性疾病的个体中,如果所残余正常的单个等位基因发生突变则会导致视网膜母细胞瘤的发生,或者在两个等位基因同时发生

原癌基因的发现改变了我们对肿瘤发生机制的认识。之后,对视网膜母细胞瘤基因(RB1)的确定则预示着另一个观念——恶性疾病的发生具有一定遗传基础,即在生殖细胞和体细胞中肿瘤抑制基因的突变会导致肿瘤的形成。事实上,对肿瘤发生的潜伏期进行分析提示,即使在“责任基因”被发现之前,我们也认识到在罹患遗传性疾病的个体中,如果所残余正常的单个等位基因发生突变则会导致视网膜母细胞瘤的发生,或者在两个等位基因同时发生突变的个体中也可能发生视网膜母细胞瘤。因此,RB1基因成为了肿瘤抑制基因的代表。
这一概念不仅意味着激活遗传事件可促进原癌基因向癌基因的转化,同时也意味着对遗传位点的抑制可导致肿瘤抑制基因的缺失,上述观点与我们既往对肿瘤的认识一致,即肿瘤的发生是一系列遗传事件的集合。肿瘤的形成或由一系列基因的随机突变造成,或来自于总基因组突变或基因组局限性突变。此外,特异的基因靶位似乎与某些特异的恶性病变相关,这意味着对于某些肿瘤而言存在着特异的基因位点,即肿瘤发生具有标志性的特征。肿瘤的发病、诊断、预后,甚至于治疗都囊括了各种遗传学特征,也就是说肿瘤可以归结为特定的遗传事件。
但是,为何特异性的遗传轨迹引起特异性的肿瘤,其原因仍令人费解。此外,我们也无法预测引起肿瘤形成以及维持肿瘤表型的遗传位点。在这样的背景之下,Diane Rushlow及其同事在《柳叶刀肿瘤学》上发表了相关研究,为视网膜母细胞瘤的发病提供了令人信服的证据,最初认为视网膜母细胞瘤形成是由于RB1肿瘤抑制基因功能缺失所造成的,现今则认为MYCN原癌基因激活也会导致视网膜母细胞瘤的发生。他们的研究结果令人惊讶,但是细想的话,其结果也是合情合理的。然而,我们必须重新考虑下述问题——即任何肿瘤的遗传基础都有可能受到多种途径的影响。
既往就有研究者指出MYCN和RB1在引起肿瘤发生的机制上存在一定联系。之前认为MYCN具有多种功能,主要是影响基因和蛋白表达,作为原癌基因其主要作用是抑制RB1旁路的作用。
在他们的研究中,Rushlow和其同事对RB1和MYCN和视网膜母细胞瘤发病之间存在的不同联系进行了评估,而不是评估两者在视网膜母细胞瘤发病之间所存在的相似点。这些疾病的发生是独一无二的吗(不仅在表型方面也在分子方面)?亦或是全然由两种不同的突变基因产物所造成?通过该研究,研究者有望对上述问题作出回答。
从试验角度来看,重建RB1可以逆转肿瘤表型。那么通过靶向抑制MYCN是否能有效治疗视网膜母细胞瘤?敲除了RB1的视网膜母细胞瘤的发病是否依赖于MYCN?由MYC扩增所介导的视网膜母细胞瘤的发病是否依赖于MYCN的持续表达?在维持肿瘤表型方面,仅有MYCN的激活能否替代RB1缺失所起到的作用?反过来,如果仅存在RB1缺失又是否能替代MYCN激活所起到的作用?只有在确定上述问题的答案之后,我们才能确定对视网膜母细胞瘤的治疗方案。
对其他遗传肿瘤的基因组分析或许也会显现出相似的结果,即肿瘤的发病是由多种因素而非单一因素所造成。这样的发现能帮助我们重新认识肿瘤的发生以及造成肿瘤发病的分子基础。随着对分子学分类的认识的扩大,我们可以探究其他以前未曾尝试过的新的治疗方案。这些分析可以揭示MYCN作为重复“基因罪犯”的本质,以及其作为潜在重要治疗靶点的价值。
视网膜相关的拓展阅读:


Role of MYCN in retinoblastoma
The discovery of proto-oncogenes transformed our insight into mechanisms of cancer. 1 Subsequently, identification of the retinoblastoma gene ( RB1 ) heralded the notion that malignant disease has a hereditary basis, by showing that both germinal and somatic acquisition of mutations in a tumour-suppressor gene causes tumorigenesis. 2 Indeed, analysis of the latency of tumour onset had predicted—even before the culprit gene was found—that retinoblastoma would arise either through a single hit in the re ...

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    2013-05-08 howi
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    2014-03-24 minlingfeng
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    2013-06-16 yulin2006
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    2013-05-05 zutt
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    2013-05-05 guihongzh
  8. [GetPortalCommentsPageByObjectIdResponse(id=1827539, encodeId=af4b182e5396c, content=<a href='/topic/show?id=1b6210686b2' target=_blank style='color:#2F92EE;'>#Lancet#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=76, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=10686, encryptionId=1b6210686b2, topicName=Lancet)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=3f0227, createdName=howi, createdTime=Wed May 08 18:37:00 CST 2013, time=2013-05-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2023456, encodeId=d1b62023456ca, content=<a href='/topic/show?id=57ce9605ef6' target=_blank style='color:#2F92EE;'>#重要作用#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=85, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=96057, encryptionId=57ce9605ef6, topicName=重要作用)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=8e4c53, createdName=jiyangfei, createdTime=Sun Feb 02 16:37:00 CST 2014, time=2014-02-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1864433, encodeId=5fb1186443385, content=<a href='/topic/show?id=16ce133504e' target=_blank style='color:#2F92EE;'>#Oncol#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13350, encryptionId=16ce133504e, topicName=Oncol)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=b63894, createdName=minlingfeng, createdTime=Mon Mar 24 16:37:00 CST 2014, time=2014-03-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1943858, encodeId=3ff8194385807, content=<a href='/topic/show?id=03811240e54' target=_blank style='color:#2F92EE;'>#MYCN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=72, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12407, encryptionId=03811240e54, topicName=MYCN)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2a44345, createdName=yulin2006, createdTime=Sun Jun 16 04:37:00 CST 2013, time=2013-06-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1772184, encodeId=79a11e721846f, content=<a href='/topic/show?id=c38963544cc' target=_blank style='color:#2F92EE;'>#母细胞瘤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=63544, encryptionId=c38963544cc, topicName=母细胞瘤)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b07438375157, createdName=huperzia, createdTime=Sat May 04 02:37:00 CST 2013, time=2013-05-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1269780, encodeId=22491269e804c, content=<a href='/topic/show?id=979690e33bd' target=_blank style='color:#2F92EE;'>#视网膜#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=58, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=90733, encryptionId=979690e33bd, topicName=视网膜)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=742793, createdName=zutt, createdTime=Sun May 05 00:37:00 CST 2013, time=2013-05-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1274786, encodeId=403c12e47864b, content=<a href='/topic/show?id=1bbc12404ba' target=_blank style='color:#2F92EE;'>#MYC#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=68, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12404, encryptionId=1bbc12404ba, topicName=MYC)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=66ec123, createdName=guihongzh, createdTime=Sun May 05 00:37:00 CST 2013, time=2013-05-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1475750, encodeId=2dd414e5750d2, content=<a href='/topic/show?id=2bcee797732' target=_blank style='color:#2F92EE;'>#细胞瘤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=65, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77977, encryptionId=2bcee797732, topicName=细胞瘤)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=bf5e7252474, createdName=spoonycyy, createdTime=Sun May 05 00:37:00 CST 2013, time=2013-05-05, status=1, ipAttribution=)]
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