肿瘤防治的新挑战 肿瘤异质性

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 160 200 220 300 110 130 155 170 250 0 50 100 150 200 250 300 350 19701991200320102020 年发病数(万) 年死亡数(万) 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，生物，初级阶段初

2、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 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

3、in 24 additional tumors. ? Pathway rather than individual genes appear to govern the course of tumorigenesis. Disruption of a 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 alte

4、rations in a similar number of pathways. A few gene mountains are mutated in a large proportion of tumors; most genes are mutated 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 codin

5、g exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancer. Most somatic mutations are likely to be passengers that do not contribute to oncogenesis. However, there was evidence for driver mutation con

6、tributing to the development of the cancer studied in approximately 120 genes. Thomas,RK et al.(Nature genetics,2007,39:347-)determined 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%) sam

7、ples carried at least one mutation 1). Wood,LD,et.al determined the 乳腺癌和结直肠癌乳腺癌和结直肠癌 DNA sequences based on exons of 20,857 transcript from 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

8、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两个肿瘤之间突变基因重复的很少 ? Pathway rather than individual genes appear to govern the course of tumorigenesis. ? Disruption of a pathway by mutation in any one of its genetic components would presumably lead to similar changes in gr

9、owth. ? The differences are likely to be the basis for the wide variation in tumor behavior and responsiveness to therapy The epigenetic progenitor model of cancer Stem/progenitor cells表观遗传学表观遗传学(epigenetic)改变改变; Gatekeeper mutation; Genetic and epigenetic instability Feinberg,AP et al.( Nature Revi

10、ew 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 CGH） 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 lym

11、phoma) 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 longer survival) Activated B-like DLBCL, to express genes normally induced during in vitro activation of peripheral blood B cells.

12、(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 treatment responses. The clinical behaviour (such as lymph node status and histological grade) fail to classify accurately ou

13、tcome. Chemotherapy or hormonal therapy reduces distant metastases by one-third, however 70-80% of these patients would not developed distant metastases without the adjuvant treatment, these patients may not benefit from the treatment, and may potentially suffer from the side effects. (Nature, 2002,

14、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 cancer will metastasize (spread to other parts of a patients body). ? 70 genes activity confers information about th

15、e 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 cellular proliferation, differentiation and apoptosis. About half of the annotated human miRNAs map within frag

16、ile 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 function as tumor suppressors and oncogenes. A single miRNA might bind as many as 200 gege targets and so, miRNAs

17、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

18、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。 N ENGL J MED 2006,355:570- N ENGL J MED 2006,355:570- Methylation of the promotor regions of P16 and CDH13 in both tumor and mediastinal lymph nodes in stage 1 NSCLC patients was associated with an odds ratio of recurrent cancer o

19、f 15.5. 有甲基有甲基化病人无复发存活时间明显病人无复发存活时间明显 低于无甲基低于无甲基化(N.ENGL.J.MED.2008,358:1118-) N0 N+ 42个基因可 区分肺癌淋 巴结转移 (50%) 分子标志谱在判断乳腺癌治疗敏感性中的应用 (北京市科委重大专项) ?通过分析新辅助化疗有效(完全缓解+部分缓解)与无效(肿瘤进展)患者治疗前后的 肿瘤组织标本以及血标本, 发现与乳腺癌化疗敏感性相关的分子标志谱。 ? 根据NCCN Clinical Practice Guidelines in Oncology (Breast Cancer, Version 1.2005) 选取

20、临床IIA（T2, N0, M0）、IIB（T2, N1, M0；T3, N0, M0）、IIIA（T3, N1, M0）期患者、其他符合保乳手术治疗的患者（除外肿瘤大小因素） 以及局部进展期乳腺癌患者(IIIA: T0-3, N2, M0; IIIB: T4, N0-2, M0; Any T, N3, M0) 入组。在接受治疗前，对入组患者进行空心针穿刺活检（core needle biopsy）取得病理诊断；随后给予4周期EC方案（表阿霉素+环磷酰胺， 14天/周期）；评价疗效 ? 运用基因芯片技术，对治疗前后标本的mRNA表达情况进行 检测、分析。比较治疗反应阳性组与治疗反应阴性组患者的

21、 上述检测指标之间的差异，寻找与新辅助化疗疗效相关的分 子标志谱，建立预测化疗疗效的临床生物学模型。 Is cancer metastasis predetermined and predictable? ?利用此153个有显 著差异的基因，在 国际上首次建立了 一个肝癌转移的预 测模型。 ?这一模型预测待检 标 本 的 准 确 率 达 90%以上。(Ye QH, et al. Nat Med, 2003, 9; 416-423) NSCLC有淋巴结转移与无淋巴结转移病人比较有淋巴结转移与无淋巴结转移病人比较, 前者前者 有有1q25-32, 12q23-24.3, 17q12-22 区域区域

22、DNA拷贝增加，而且这种差别在原位癌拷贝增加，而且这种差别在原位癌 阶段即已形成阶段即已形成, 提示在原位癌阶段即可能巳经有与转移相关的提示在原位癌阶段即可能巳经有与转移相关的driver genes 在不断推在不断推 动以后的肺癌动以后的肺癌 转移转移 (J ,Ma. et al. J Pathl 2006, 210: 205-213), 癌前病变与癌癌前病变与癌 癌变的多阶段发生模式 从正常细胞发展到危及生命的恶性肿瘤，大多经历“癌前病变” 阶段。而从“癌前病变”发展成侵袭性癌一般需要 10年或更长的时 间，“癌前病变”的一个重要特征是具有可逆性。 正常 增生 轻度 不典型增生 原位癌 侵

23、袭癌 转移癌 1030 年 癌前病变 1570%宫颈原位癌在10年后会发 展成浸润癌；大约在3.54.5年中， 16%的宫颈轻度不典型增生发展成重度 不典型增生及原位癌。 正常或浅表性胃炎 慢性萎缩性胃炎 肠上皮型化生 异型增生 胃癌 胃粘膜多阶段癌变过程 异型增生发生癌变的 危险度增加41倍多； 控制癌前病变 1950年以来，巴氏涂片检测宫颈癌前 病变加上外科切除，使宫颈癌发生率和死 亡率分别下降78和79，而未实施这项 措施的国家, ,宫颈癌仍然是妇女肿瘤的主要 死亡原因。 20mg/day (6682人) 对照对照(6706人) 69个月后 22/1000 43.4/1000 49岁下降

24、44%; 50-59组降51%; 60组降组降55% 原位癌组降56%;不典型增生组降不典型增生组降86% Estrogen受体阳性组降69% Estrogen受体阴性肿瘤无明显影响受体阴性肿瘤无明显影响 子宫内膜癌危险性上升 Stage1 Tamoxifen ? 为什么有些癌前病变会发展成为浸袭性癌？而 大部分不会？ ? Molecular lesions that occur in early stage of cancer or in precursor lesions are more likely to have a direct influence (Drivers) on cancer occurrence and progression than those that accumulate at the later stage of cancer development. Among the latter, many alterations may be considered as passengers 早期癌变预警标志 肿瘤早期发现和诊断肿瘤早期发现和诊断 是肿瘤治疗的关键是肿