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1、肿瘤防治的新挑战 (肿瘤异质性, 分子分型, 及个体化冶疗),中国医学科学院 北京协和医学院肿瘤研究所 肿瘤医院程书钧,我国恶性肿瘤发病及死亡情况的回顾与预测,预计在2020年，全球新发病例将达1500万(我国占1/5)，死亡1000万(我国占1/4)，现患病例3000万。,肿瘤防治模式,高危个体 癌前病变 占位病变 预防 予警、发现 手术、放疗、化疗生物，初级阶段,Wood,LD,et.al(Science,2007,Nov.16,Vol.318:1108) isolated DNA from 11 breast and 11 colorectal tumors and determined
2、 the sequences based on exons representing 20,857 transcript from 18,191gene. Any gene that was mutated in the tumor but not in normal tissue from the same patients was analyzed in 24 additional tumors.Pathway rather than individual genes appear to govern the course of tumorigenesis. Disruption of a
3、 pathway by mutation in any one of its genetic components would presumably lead to similar changes in growth. The 15 driver mutation in an individual tumor likely reflect alterations in a similar number of pathways.,A few gene mountains are mutated in a large proportion of tumors; most genes are mut
4、ated in 5% of tumors represented as hills两个肿瘤突变基因重复的很少， (Science 2007,318: 1108),Greenman,C et al(Nature, 2007,446:153-)reported 1,000 somatic mutations found in the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mu
5、tations in individual cancer. Most somatic mutations are likely to be passengers that do not contribute to oncogenesis. However, there was evidence for driver mutation contributing to the development of the cancer studied in approximately 120 genes.,Thomas,RK et al.(Nature genetics,2007,39:347-)dete
6、rmined 238 known oncogen mutation across 1,000 human tumor samples of 17 cancer types. Of 17 oncogens analyzed, they found 14 to be mutated at least once, and 298(30%) samples carried at least one mutation,1). Wood,LD,et.al determined the 乳腺癌和结直肠癌 DNA sequences based on exons of 20,857 transcript fr
7、om 18,191gene. (Science,2007,Nov.16,Vol.318:1108) 2). Thomas RK,et al 分析17类肿瘤 238个oncogenes 的突变(Nature genetics, 2007: 39; 153-)3). Greenman,C;et al. 分析210个不同人的肿瘤的 518 protein kinase gene exons 的突变 ( Nature, 2007, 446: 153-)两个肿瘤之间突变基因重复的很少Pathway rather than individual genes appear to govern the cou
8、rse of tumorigenesis. Disruption of a pathway by mutation in any one of its genetic components would presumably lead to similar changes in growth. The differences are likely to be the basis for the wide variation in tumor behavior and responsiveness to therapy,The epigenetic progenitor model of canc
9、er Stem/progenitor cells表观遗传学(epigenetic)改变; Gatekeeper mutation; Genetic and epigenetic instability Feinberg,AP et al.( Nature Review Genetics,2006,7: 21-33),我们还不清楚一个肿瘤包含有多少个基因的改变，以及相互的作用机理？但研究已揭示与癌变有关的基因参与的复杂性，造戌了肿瘤病人的个体反应不同，这是肿瘤分子分型和个体化冶疗的基础,肿瘤异质性, 分子型, 及个体化冶疗 Systems biology,基因突变谱 (SNP) （Array C
10、GH） 基因组甲基化谱 基因表达谱 MicroRNAs谱(Oncomirs) 蛋白标志谱 染色体异常 细胞组织,Diffuse large B-cell(DLBCL)(the most common subtype of non-Hodgkins lymphoma) Germinal centre B-like DLBCL, to express genes characteristic of germinal centre B cell, had a significant better survival.(LMO2, BCL6,FN1, expression related to long
11、er survival) Activated B-like DLBCL, to express genes normally induced during in vitro activation of peripheral blood B cells. (CCND2, SCYA3, BCL2. expression related to shorter survival) ( N. Engl. J. Med. 2004, 300: 1828-1837),Breast cancer patients with the same stage can have markedly different
12、treatment responses. The clinical behaviour (such as lymph node status and histological grade) fail to classify accurately outcome. Chemotherapy or hormonal therapy reduces distant metastases by one-third, however 70-80% of these patients would not developed distant metastases without the adjuvant t
13、reatment, these patients may not benefit from the treatment, and may potentially suffer from the side effects.(Nature, 2002,VOl.415, 530),FDA News FOR IMMEDIATE RELEASE P07-13 February 6, 2007 Media Inquiries: . The MammaPrint test uses the latest in molecular technology to predict whether existing
14、cancer will metastasize (spread to other parts of a patients body).70 genes activity confers information about the likelihood of tumor recurrence.,MicroRNA(miRNAs 300-1000) are an abundant class of negative gene regulators that have been shown to control a wide range of biological functions such as
15、cellular proliferation, differentiation and apoptosis. About half of the annotated human miRNAs map within fragile region of chromosomes, which are areas of the genome that are associated with various human cancers. miRNA mutations or mis-expression correlate with various human cancers and can funct
16、ion as tumor suppressors and oncogenes.A single miRNA might bind as many as 200 gege targets and so, miRNAs potentially control the expression of about one-third of human mRNAs .Nature Reviews/ Cancer 2006, 6;259-269,Lu et al.( Nature,2005 435:834-),约25%临床诊断为肺癌Ia期患者，单纯接受手术治疗后会复发。因此有必要识别此亚型的患者，以便给予更有效的治疗。 Potti等（ N Engl J Med 2006, 355:570- ）用89例早期NSCLC病例构建了一个“肺癌转移模型”表达谱芯片(准确率93%, ，高于目前应用的基于临床病理特征的预测方法 64%) ，并可鉴别出需要术后化疗的Ia期患者。 该研究已被美国临床肿瘤学会（ASCO）评为2006年临床肿瘤研究主要进展之一。,
