青海大学附属医院结直肠癌课件

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,二级,三级,四级,五级,*,*,基因检测在结直肠癌治疗中的意义,青海大学附属医院,胃肠外科,恶性肿瘤发病率与死亡率呈上升趋势,前十位恶性肿瘤死亡率,(,合计,),顺位,2004-2005,1990-1992,1973-1975,疾病名称,死亡率,(1/10,万,),疾病名称,死亡率,(1/10,万,),疾病名称,死亡率,(1/10,万,),1,肺癌,30.83,胃癌,25.16,胃癌,19.54,2,肝癌,26.26,肝癌,20.37,食管癌,18.83,3,胃癌,24.71,肺癌,17.54,肝癌,12.54,4,食管癌,15.21,食管癌,17.38,肺癌,7.09,5,结直肠癌,7.25,结直肠癌,5.30,子宫颈癌,5.23,6,白血病,3.84,白血病,3.64,结直肠癌,4.60,7,脑瘤,3.13,子宫颈癌,1.89,白血病,2.72,8,女性乳腺癌,2.90,鼻咽癌,1.74,鼻咽癌,2.32,9,胰腺癌,2.62,女性乳腺癌,1.72,女性乳腺癌,1.65,10,骨癌,1.70,恶性肿瘤总计,134.80,恶性肿瘤总计,108.26,恶性肿瘤总计,83.65,摘自：卫生部网站,结直肠癌病理分型,结直肠癌发生发展遗传模型,结直肠癌不同阶段生存期,EGFR,分子信号通路对肿瘤细胞影响,EGFR,信号通路与,EGFR,靶向治疗,EGFR,信号通路与相关靶向药物,KRAS,突变与爱必妥总生存率,metastatic colorectal cancer,Michel Ducreux,et al.,Cancer Res,2006,E.Van Cutsem,et al.,ECCO 15,-,ESMO 34,2009,KRAS,突变与爱必妥无病情发展生存率和总生存率,Progression-free survival,Overall survival of the 113 pooled,patients according to the presence or absence of,KRAS mutation(P=1.4*10,-7,and,P=0.0017,respectively).,colorectal cancer,Astrid Lievre,et al.,JOURNAL OF CLINICAL ONCOLOGY,.2008(26),374,KRAS,突变与爱必妥药效,V.Heinemann et al.,Cancer Treatment Reviews,2009,colorectal cancer,KRAS BRAF,突变与爱必妥响应率,metastatic colorectal cancer,F Loupakis,et al.,British Journal of Cancer,2009,BRAF,突变与爱必妥无病情发展生存率和总生存率,Fig 1.(A)Progression-free survival and(B)overall survival in wild-type KRAS patients according to BRAF status.M,mutated;NM,nonmutated.,Pierre Laurent-Puig,et al.,J Clin Oncol,2009,PIK3CA,突变与,EGFR,单抗疗效,panitumumab/cetuximab,metastatic colorectal cancer,Andrea Sartore-Bianchi,et al.,Cancer Res,2009,PIK3CA,突变与结肠癌手术患者预后关系,resectable colon cancer(stage I to III),Ogino,et al.,J Clin Oncol,2009,PTEN,表达与,EGFR,单抗疗效,panitumumab/cetuximab,metastatic colorectal cancer,Andrea Sartore-Bianchi,et al.,Cancer Res,2009,PIK3CA,突变、,PTEN,表达与,EGFR,单抗疗效,panitumumab/cetuximab,metastatic colorectal cancer,Andrea Sartore-Bianchi,et al.,Cancer Res,2009,EGFR,扩增，,KRAS,、,BRAF,突变，,PTEN,表达与爱必妥疗效,Pierre Laurent-Puig,et al.,J Clin Oncol,2009,小结：相关标记物与爱必妥疗效,Russo et al;Oncology 2009,Russo et al;Oncology 2009,血管生成是恶性肿瘤快速增长所必须的,Stages at which angiogenesis plays a role in tumor progression,Premalignant,stage,Malignant,tumor,Tumorgrowth,Vascularinvasion,Dormantmicrometastasis,Overtmetastasis,(Avascular,tumor),(Angiogenicswitch),(Vascularizedtumor),(Tumor cellintravasation),(Seeding indistant organs),(Secondary,angiogenesis),Adapted from Poon RT,et al.,J Clin Oncol,.2001;19:120725,血管生成相关因子,Tumour Cells,PDGF,VEGF,PDGFReceptor,VEGF Receptor,FGF Receptor,FGF,Hostcells,CO,2,Hypoxia,COX-2,NO,src,HER2/neu,ras P53,VHL Oxidative Stress,MitoticSpindle,Signal Transduction Cascade,Proliferation,Invasion,Migration,Degradation of basement membrane,Permeability,Capillary tube formation,VEGF,信号通路与血管生成,针对,VEGF,基因家族的靶向药物,针对,VEGF,基因家族靶向治疗临床试验,Lee M.Ellis,et al.,NATURE REVIEWS cancer,2008,Nishan H.F.,et al.,The Oncologist.,2004(9 suppl 1),11.,靶向,VEGF,基因治疗药物贝伐单抗,colorectal cancer,KRAS,突变与贝伐单抗药效,randomized phase III,：,AVF2107,metastatic,colorectal cancer,ROSEN,et al.,The Oncologist,2009,EGFR,、,ERCC1,表达与伊立替康疗效,PFS,OS,EGFR,、,ERCC1,高表达（,mRNA,水平）的患者采用对应治疗方案具有更长的生存期，其中,PFS,差异显著。,Daniel,et al.,Int.J.Cancer,2006,ERCC1,密码子,118 CT,多态性与铂类药物疗效,Chang,et al.,Cancer Sci,2009,metastatic,colorectal cancer,ERCC1,密码子,118 CT,多态性影响蛋白表达水平,Chang,et al.,Cancer Sci,2009,TYMS,表达与氟类药物疗效相关性,Patrick G.Johnston,et al.,CANCER RESEARCH,.,1995(55),1407,colorectal cancer,gastric cancer,ERCC1/TS,基因表达联合检测,Yoshinori Shirota,et al.,Journal of Clinical Oncology.,2001(19),4298.,5-FU/oxaliplatin,metastatic,colorectal cancer,结直肠癌潜在治疗靶点,个性化治疗及分子检测导致的变革,过去,标准化的治疗方案未来,个性化的治疗方案,分子检测,有响应患者,无响应患者,存活率受益,毒性反应而,存活率没有受益,延误有效治疗,有响应患者,无响应患者,存活率受益,毒性反应而,存活率没有受益,延误有效治疗,给适合,的患者,正确的治,疗方案,化疗药,敏感度（,+,）,敏感度（,-,）,敏感度（,+,）,敏感度（,-,）,更合理的癌症个性化治疗和临床试验方案,分子检测在癌症个性化治疗中的应用,风险评估,早筛,诊断,分期,预后评估,治疗选择,疗效监测,复发监控,第一代分子诊断,更高价值的第二代应用,靶向治疗所需的,(,组织活检,),基本生物分析,方法,原理,优点,缺点,寡核苷酸探针法,PCR,，探针特异,操作简便，易于标准化，检测周期短,敏感性相对较低,限制性片段,长度多态性,突变使,DNA,分子的限制酶切位点改变,敏感度高，可达,0.1%,非定量，特异性差，检测周期长,高分辨熔解曲线分析,含突变序列的样本特定温度熔解曲线不同,对引物设计没有要求,操作复杂，不易标准化，检测周期长,扩增受阻突变体系,PCR,，引物特异,敏感度较高，检测周期短,效率低,，引物设计要求严格,直接测序法,非特异性突变序列检测,最终确定突变检测的金标准,定量差，成本高，检测周期长,中国抗癌协会推荐的标准方法,优化的,定量,寡核苷酸探针法,主要基因突变检测方法比较,优化的定量寡核苷酸探针法,优化后将灵敏度提高到,1%,的水平,高灵敏度,目前国内外唯一的,定量,方法,精确定量,新鲜组织样本,组织切片（蜡块）,血液、胸腔积液,多种样本,突变,+,表达检测,定性,+,定量检测,预后指标检测,疗效监测、复发监测,多种应用,专利技术,K-ras,野生型,DNA,标准曲线的确定,K-ras,突变型,DNA,标准曲线的确定,突变检测定性与定量的对比,突变比例,定性试验结果,定量实验结果,1%,阳性,突变,%+,阳性,定量突变检测的意义,Okami J,Taniguchi K,Higashiyama M,et al,Oncology,2007;72:234242,Progression-free(c)and overall survival(d)in patients with the EGFR mutation.Patients were divided into two groups according to the ratio of mutated EGFR transcripts,高突变比例组,低突变比例组,Thank You!,