基因分型在肝胆肿瘤的探索与实践课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,基因分型在肝胆肿瘤的探索与实践,基因分型在肝胆肿瘤的探索与实践,肿瘤精准治疗：肿瘤的分子水平理解和分类,针对,driver mutation,进行治疗在肝胆肿瘤中的应用,肝胆肿瘤精准治疗的探索篇,肿瘤精准治疗：肿瘤的分子水平理解和分类,针对,driver mutation,进行治疗在肝胆肿瘤中的应用,肿瘤精准治疗：肿瘤的分子水平理解和分类肝胆肿瘤精准治疗的探索,检测方法推动肿瘤治疗的发展,组织学检测集中在对于形态学的研究,病理检测,人群中发生频率较高的驱动变异被作为作为研究重点,基因变异热点检测,高通量二代测序,NGS,多基因、全部位点、多种变异形式同时检测,放疗结合化疗,不同组织类型肿瘤选择差异性化疗药物，毒副作用高，疗效趋于极限,靶向个性治疗,适应症内,biomarker,筛选,阳性人群大部分获益，生存大大提高,精准医学,深入阐明癌症基因组的异质性特征，,精确找到每个患者疾病的原因和治疗的靶点,检测方法推动肿瘤治疗的发展组织学检测集中在对于形态学的研究病,精,准医学建立在肿瘤异质性的理论基础上,肝癌中的基因变异涉及多条不同信号通路的基因,约,30,个基因在,243,例肝癌样本的,WES,检测中突变频率超过,4%,Nat Genet.2015 May;47(5):505-11.,精准医学建立在肿瘤异质性的理论基础上肝癌中的基因变异涉及多条,肝内，肝外胆管癌和胆囊癌分子水平的,异同,肝内，肝外胆管癌和胆囊癌分子水平的异同,大样本量,NGS,检测揭示胆道肿瘤变异图谱,Cancer.2016 Sep 13.doi:10.1002/cncr.30254.,Intrahepatic,cholangiocarcinoma(n=412),extrahepatic,cholangiocarcinoma,(n=57),gallbladder carcinoma,(n=85),大样本量NGS检测揭示胆道肿瘤变异图谱Cancer.201,肝内胆管癌不同分子亚型的临床意义,TP53 mutation,OS:226vs140 wks,KRAS mutation,OS:214vs166 wks,FGFR2 mutation,OS:NA vs 187 wks,Cancer.2016 Sep 13.doi:10.1002/cncr.30254.,肝内胆管癌不同分子亚型的临床意义TP53 mutationK,驱动基因变异的个体化差异明显,Gastroenterology.2016 Apr;150(4):998-1008.,同一病人多病灶之间基因变异共享率从,0-97%,不等,驱动基因变异的个体化差异明显Gastroenterology,驱动基因变异的个体化差异明显,Gastroenterology.2016 Apr;150(4):998-1008.,“Variability is the law of lifeno two individuals react alike and behave alike under the abnormal conditions which we know as disease”,-Sir William Osler,address to the New Haven Medical Association in 1903,驱动基因变异的个体化差异明显Gastroenterology,肿瘤精准治疗：肿瘤的分子水平理解和分类,针对,driver mutation,进行治疗在肝胆肿瘤中的应用,肝胆肿瘤精准治疗的探索篇,肿瘤精准治疗：肿瘤的分子水平理解和分类肝胆肿瘤精准治疗的探索,Meta,分析提示不同瘤种的个体化治疗疗效均优于常规抗肿瘤治疗,570,个筛选,biomarker,的单药物靶向治疗的,phase II,临床研究（,32,149,病人）,2010.1.1,至,2012.12.31,期间发表的结果,研究终点：有效率,(RR),，无疾病进展期,(PFS),和总生存,(OS),J Clin Oncol.2015 Nov 10;33(32):3817-25.,Meta分析提示不同瘤种的个体化治疗疗效均优于常规抗肿瘤治疗,肝内，肝外胆管癌和胆囊癌分子水平的,异同,肝内，肝外胆管癌和胆囊癌分子水平的异同,胆道肿瘤中的抗,HER2,靶向治疗,J Hematol Oncol.2015 May 29;8:58.,胆道肿瘤中的抗HER2靶向治疗J Hematol Oncol,FGFR,通路变异患者从,FGFR,靶向治疗获益,Cancer.2016 Sep 13.doi:10.1002/cncr.30254.,FGFR通路变异患者从FGFR靶向治疗获益Cancer.2,Ecancermedicalscience.2014 Nov 6;8:479.,PET scan before(upper panel A)and two months after dabrafenib and trametinib combination(lower panel B),showing improvement in liver metastasis(blue arrow),resolution of malignant left pleural effusion and lung nodules(red arrow)and improvement of bone metastasis(blue circle).,Ecancermedicalscience.2014 No,免疫微环境对肿瘤的调控与杀伤,Liver Cancer.2015 Dec;4(4):201207.,免疫微环境对肿瘤的调控与杀伤Liver Cancer.20,肿瘤突变负荷（,TMB,）可能作为抗,PD-1,治疗的,biomarker,J Clin Oncol 34,2016(suppl;abstr 9017),肿瘤突变负荷（TMB）可能作为抗PD-1治疗的biomark,MMR,缺陷提示可能从抗,PD-1,治疗获益,N Engl J Med.2015 Jun 25;372(26):2509-20.,MMR缺陷提示可能从抗PD-1治疗获益N Engl J Me,精准治疗在技术上以二代测序（,NGS,）为主凸显优势,NGS,检测,突变,插入,/,缺失,TMB,基因重排,扩增,/,缺失,ARMs,ddPCR,一代测序,FISH,转录水平变化,蛋白表达异常,IHC,protein,RNA,DNA,基因融合,精准治疗在技术上以二代测序（NGS）为主凸显优势NGS检测突,NGS identifies actionable genomic alterations in“,driver-negative,”lung adenocarcinomas,：,no mutations in EGFR,ERBB2,KRAS,NRAS,BRAF,MAP2K1,PIK3CA,and AKT1 and fusions involving ALK,ROS1,and RET),A genomic alteration with a corresponding targeted therapeutic based on the NCCN guidelines for NSCLC was identified in,26%of patients(8/31,),EGFR,G719A,BRAF,V600E,SOCS5,-,ALK,CLIP4,-,ALK,CD74,-,ROS1,KIF5B,-,RET,(n=2)and,CCDC6,-,RET,Of these 8 patients,75%(n=6),went on to receive their targeted therapy,and all six of these patients derived clinical benefit from targeted therapy.,Alexander Drilon,et al,CCR,2015;Balko JM,et al,Cancer Dis,2015;Siraj M,et al,ASCO,2014,二代测序,vs,传统检测方法,NGS identified,7/81(,8.6%,)TNBC,patients with,ERBB2,gene amplification which was confirmed by FISH in both the pre-and post-treatment tissue,.,32%of ALK,rearranged cases as identified by NGS previously tested negative by FISH(9/28).,70%of the FISH negative patients from this study treated with crizotinib responded demonstrating the ALK rearrangements detected by NGS are acting as a oncogenic driver,NGS identifies actionable geno,全美前十癌症医院的,NGS,检测平台,排名,中心名称,床位,NGS,基因检测,基因数量,开始时间,1,University of Texas MD Anderson Cancer Center,654,-,200 genes,2013,2,Memorial Sloan Kettering Cancer Center,478,MSK-IMPACT,341 genes,2014,3,Mayo Clinic,1243,CANCP,50 genes,2014,4,Dana-Farber/Brigham and Womens Cancer Center,757,OncoPanel,300 genes,2013,5,Seattle Cancer Care Alliance/University of Washington Medical Center,428,UW-OncoPlex,263 genes,2013,6,Johns Hopkins Hospital,998,NGS 50 gene panel,50 genes,2015,7,UCLA Medical Center,466,clinical exome sequencing,20,000 genes,2015,8,Massachusetts General Hospital,999,SNaPshot,39 genes,2013,9,UCSF Medical Center,650,UCSF500,429 genes,2015,10,Stanford Health Care-Stanford Hospital,481,-,-,-,全美前十癌症医院的NGS检测平台排名中心名称床位NGS基因检,NGS,检测关键步骤,生信后分析,确认测序质量及生信分析变异,calling,真伪，鉴定明确的体细胞基因变异（包括,SNV/Indel,，,CNV,，重排,/,融合和大片段,Indel,）,QC,分析变异造成的功能影响：临床数据,(,药物响应,),，临床前实验数据，计算生物学预测的,driver,或者,passenger,变异,Knowledge Databa