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1、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,检测方法推动肿瘤治疗的发展,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.,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 S
2、ep 13.doi:10.1002/cncr.30254.,Intrahepatic cholangiocarcinoma(n=412),extrahepatic cholangiocarcinoma(n=57),gallbladder carcinoma(n=85),肝内胆管癌不同分子亚型的临床意义,TP53 mutationOS:226vs140 wks,KRAS mutationOS:214vs166 wks,FGFR2 mutationOS:NA vs 187 wks,Cancer.2016 Sep 13.doi:10.1002/cncr.30254.,驱动基因变异的个体化差异明显,G
3、astroenterology.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.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 Hav
4、en Medical Association in 1903,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,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.,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HE
5、R2靶向治疗,J Hematol Oncol.2015 May 29;8:58.,FGFR通路变异患者从FGFR靶向治疗获益,Cancer.2016 Sep 13.doi:10.1002/cncr.30254.,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
6、),resolution of malignant left pleural effusion and lung nodules(red arrow)and improvement of bone metastasis(blue circle).,免疫微环境对肿瘤的调控与杀伤,Liver Cancer.2015 Dec;4(4):201207.,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),MMR缺陷提示可能从抗PD-1治疗获益,N Engl J Med.2015 Jun 25;372(26):2
7、509-20.,精准治疗在技术上以二代测序（NGS）为主凸显优势,基因融合,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
8、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-RETOf 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.,Alexa
9、nder 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 test
10、ed 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,全美前十癌症医院的NGS检测平台,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
11、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,根据证据等级选择相关靶向药物(直接相关或者间接相关),Take home messages,NGS技术的发展帮助我们更好的了解肝胆肿瘤的生物学特性，并细分病人群体在肝胆肿瘤中已有初步研究及实践提示针对driver变异使用靶向治疗是潜在的临床治疗机会免疫治疗作为新兴的肿瘤治疗手段，急需找到明确的biomarker来筛选人群，少量临床证据提示TMB或者MSI可能作为潜在biomarkerNGS在检测肿瘤基因变异中具有同时检测多种变异形式和高通量的技术优势NGS临床检测技术的关键步骤在于生信后的进一步数据分析,Thank You,领航分子诊断技术提升医学检测服务,Thank You,
