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Science | 白凡/徐涛课题组合作揭示癌旁正常上皮组织存在大量突变及克隆扩增

日期: 2020-10-02

rentineigezhongzhengchangzuzhizhongdexibaodouzaibukebimiandejileitubian。zheixietixibaotubiandefashengtongchangyuxibaofenlieguochengzhongdnadefuzhicuowumeiyoudedaoxiufu,huomeiyoudedaozhengquedexiufuxiangguan。tongchangqingkuangxia,zheixietubianbuhuiduitixibaodebiaoxinghegongnengzaochengmingxianyingxiang,ranerruguobufentubianfashengzaiyixieyuxibaozengzhihesiwangxiangguandezhongyaojiyinshangshi,xiedaitubiandetixibaohenkenengyincihuodeshengzhanghejingzhengshangdeyoushi,congerzaochengtixibaotubiankelongdexingchenghekuozhang,zuizhongdaozhijibingheshuailaoguochengdefasheng。zuiguangweishuzhideyigelizijiushiaizhengdefasheng,jitixibaozaineiyuanhuowaiyuanyinsudezuoyongxiazhujianjileitubianbingfashengkelongkuozhang,zuizhongdaozhiaizhengdechansheng。yinci,yanjiuzhengchangzuzhizhongtixibaotubianjileideguochengjitubiankelongdekuozhangjiyanhua,duiyugenghaodilijieaizhengdezaoqifashengfazhanjuyouzhongyaodeyiyi。

2020nian10yue2ri,yabodianzijingjishengwuyixueqianyanchuangxinzhongxin(biopic)、yabodianjingbaifanketizuyuyabodianzijingjirenminyiyuanminiaowaikexutaoketizuhezuozaiguojizhumingxueshuqikansciencezazhishangyiresearch article(yanjiuzhangwen)xingshifabiaotiwei“macroscopic somatic clonal expansion in morphologically normal human urothelium” deyanjiulunwen。gaigongzuoxitongdiyanjiulezuzhixingtaizhengchangdeniaolushangpizuzhizhong,tixibaotubian(somatic mutations)defashengyujilei,yijitubiankelongdekuozhangheyanhuaguilv。

尿路上皮组织是膀胱和输尿管中的一种“移行上皮组织”。尿路上皮组织的更新速率较快且在受损情况下会迅速再生[1]。在2017年的一项关于多病灶尿路上皮肿瘤基因组的研究工作中,白凡和徐涛课题组在其中一个病例的组织形态学正常的尿路上皮组织中检测到了大量的体细胞突变[2]。这个偶然的发现促使两个课题组开展针对组织形态正常的尿路上皮组织中体细胞突变积累这个问题的更加深入和全面的科学研究。

在本项研究中,研究人员使用激光显微切割和全外显子深度测序技术,对来自于120个尿路上皮肿瘤病例的126个肿瘤组织以及161个组织形态学正常的癌旁尿路上皮组织进行了深入的研究。通过外显子数据分析,研究人员发现在部分组织形态学正常的尿路上皮组织中,已积累大量的体细胞突变。让人意外的是,很多突变已经发生在与肿瘤相关的驱动基因上。然而与肿瘤相比,形态正常尿路上皮组织中的驱动基因突变主要集中在与染色质重塑(chromatin remodeling)相关的基因上(例如:KMT2D基因和KDM6A基因),而较少发生在肿瘤中高频突变的关键驱动基因上(例如:PIK3CA基因和FGFR3亚博电竞基因)。这个差异反映了尿路上皮组织中早期克隆发展和最终尿路上皮癌的形成具有潜在的不同分子机制 (图1)。

1,尿路上皮癌及正常尿路上皮组织的体细胞突变图谱

jiexialai,yanjiurenyuantongguoduidanjianjitubiantezheng(single-base-substitution mutational signature)defenxijiexiledaozhizhengchangniaolushangpizuzhijileidaliangtixibaotubiandeqianzaiyuanyin。yanjiurenyuanfaxiantubiantezhengsbs1,sbs2,sbs13,sbs5yijisbs22junyidingchengdudaozhilezhengchangniaolushangpizuzhizhongtubiandefasheng。qizhong,sbs22daozhilebenyanjiuzhongdaduoshuzhengchangniaolushangpizuzhizhongtubiandefasheng。yiwangyanjiubiaoming,sbs22duiyingdezhiaiyinsushiyoubianjimadoulingsuan(aristolochic acid, aa)dezuoyong,yijingbeiguangfandibaodaoyuganaihebangguangaidengzhongliudefashengxiangguan[3, 4]。benxiangyanjiugongzuojieshilemadoulingsuandezhibianzuoyongnenggoudaozhizhengchangniaolushangpizuzhijileidaliangdetubiancongercushikelongdekuozhang。

亚博电竞 tongguoduiwaixianzishujudejinyibuwajue,yanjiurenyuanfenxilezhengchangniaolushangpizuzhizhongjiyinkaobeishubianyi(copy number alterations)deqingkuang (tu2)。yutixibaotubiandeqingkuangbutong,kaobeishubianyiyouqishijiyinzudafanweikaobeishubianyijiaoshaochuxianyuxingtaizhengchangniaolushangpizuzhizhong。shenzhizaineixieyijingxiedaidaliangtubianyijiqudongjiyintubiandeniaolushangpizuzhizhong,kaobeishubianyiyehenshaofasheng。zheixiangjieguoxianshi,jiyinzuwendingxinghekaobeishubianyishizhengchangshangpizuzhihezhongliuzuzhizhijianmingxiandequbie,jinjintubiandejileihuoxubuzuyidaozhizhengchangshangpixiangexingzhongliudezhuanhua。

2,尿路上皮癌及正常尿路上皮组织中的拷贝数变异事件

在进一步针对突变负荷(mutational burden)和克隆扩张的分析中,研究人员将正常尿路上皮组织分为两组:AA导致突变组和其他因素导致突变(非AA组)。通过对比AA组和非AA组,发现AA组尿路上皮组织的突变负荷接近尿路上皮癌的突变负荷,且比非AA组尿路正常上皮组织的突变负荷高出一个数量级。基于体细胞突变占比,研究人员推算了两组正常尿路上皮组织中克隆扩张的大小,结果发现AA组中的克隆扩张大小显著的高于非AA组的克隆大小。上述两方面的分析反映了AA促进了正常尿路上皮细胞中突变的积累以及尿路上皮组织中克隆的扩张(图3)。

3,正常尿路上皮组织中突变克隆的突变负荷及克隆大小研究

zuihou,tongguoxitongfashengshudegoujianyijitubianxibaobilidejisuan(mutant cell fractions)fenxi,yanjiurenyuanzhonggoulebufenbinglizhonghuoqudeduogezhengchangniaolushangpizuzhizhijiandekelongguanxi。jieguoxianshizaiyixiebinglizhong,duogezhengchangniaolushangpizuzhidetubiankelongduliqiyuanbingdulikuozhang、yanhua,jileiwanquanbutongdequdongjiyintubian;danzaigebieteshubinglizhong,yanjiurenyuanfaxianyouaazuoyongyinqidetubiankelongfashenglejuliedekuozhang,kelongdaxiaodadaolejingrendepingfanglimijibie(tu4)。

4,正常尿路上皮组织中突变克隆的克隆关系及扩张演化研究

zongshangsuoshu,benxiangyanjiujiehejiguangxianweiqiegejishuhequanwaixianzishenducexujishu,shenruxitongdeyanjiuleaipangzuzhixingtaixuezhengchangdeniaolushangpizuzhizhongtixibaotubiandejileiyijitubiankelongdekuozhangheyanhua,goujianlequanmiandezhengchangniaolushangpixibaotubiantupu,weijinyibulijieniaolushangpiaiyizhiqitazhongliudezaoqifashengtigonglezhongyaodezhishi。tebieshi,benyanjiuzhongzaixingtaizhengchangshangpizuzhizhongguanchadaodedaliangtubianjileihekelongkuozhang,jiangyinfazhongliuxibaoshengwuxuebiaoxingyujiyintubianzhijianruheduiyingdeshencengsikao。

亚博电竞 yabodianzijingjishengwuyixueqianyanchuangxinzhongxin(biopic)boshihouliruoyan(xiangongzuoyuyingguojianqiaowellcome sanger institute)、boshiyanjiushengchenzhanghua、boshiyanjiushengxudeshu、yabodianzijingjirenminyiyuanduyiqingboshiyijizhongshandaxuesunyixianjinianyiyuanlintianxinjiaoshouweibenwendebingliediyizuozhe。yabodianzijingjishengwuyixueqianyanchuangxinzhongxin(biopic)、shengmingkexueyuanbaifanyanjiuyuanheyabodianzijingjirenminyiyuanxutaojiaoshouweigaiyanjiulunwendegongtongtongxunzuozhe。gaiyanjiuxiangmudedaoleguojiazhongdianyanfajihua、guojiakejizhongdazhuanxiang、guojiazirankexuejijindengdezhichi。

亚博电竞 yuanwenlianjie:

参考文献:

1.     S. C. Baker, J. Southgate, “Bladder tissue regeneration” in Electrospinning for Tissue Regeneration (Woodhead Publishing Series in Biomaterials, 2011), pp. 225-241.

2.     Y. Du et al., Mutagenic factors and complex clonal relationship of multifocal urothelial cell carcinoma. European Urology 71, 841-843 (2017).\

3.     A. W. T. Ng et al., Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia. Science Translational Medicine 9亚博电竞, eaan6446 (2017).

4.     S. L. Poon et al., Mutation signatures implicate aristolochic acid in bladder cancer development. Genome Medicine 7亚博电竞, 38 (2015).