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1、CancerMolecular Network DiseaseCheng shujun, Gao yanning, Cheng shujun, Gao yanning, Zhang kaitai, Xiao Tin Zhang kaitai, Xiao TinCancer Institute, Chinese Academy of Medical Cancer Institute, Chinese Academy of Medical Sciences, Peking Union Medical CollegeSciences, Peking Union Medical CollegeFort
2、une Magazine, March 22,2004 Personalized Therapy progress and challengeBreast 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 outcome. Chemotherapy or hormonal t
3、herapy 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,VOl.415, 530)Breast cancer patien
4、ts 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 outcome. Chemotherapy or hormonal therapy reduces distant metastases by one-third, however 70-80% of these patients would not
5、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,VOl.415, 530)FDA NewsFOR IMMEDIATE RELEASEP07-13February 6, 2007 Media Inquiries: .The MammaPrint test uses the latest in mo
6、lecular technology to predict whether existing cancer will metastasize (spread to other parts of a patients body). 70 genes activity confers information about the likelihood of tumor recurrence. Imatinib(Glivec) Chronic myelogenous leukemia(CML) Bcr-abl tyrosine kinase inhibitor . CML patients have
7、high-expression of Bcr-abl fusion protein. Gefitinib (Iressa) (epidermal growth factor receptop tyrosine kinase inhibitor) Lung adenocarcinoma patients with relatively high frequency of EGFR gene mutation Herceptin Breast cancer Her2 monoclonal antibody Ttumor regression 11-26% for unselected Ttumor
8、 regression 11-26% for unselected Ttumor regression 11-26% for unselected Ttumor regression 11-26% for unselected breast cancer patients,breast cancer patients,breast cancer patients,breast cancer patients, 34% for HER2-positive 34% for HER2-positive 34% for HER2-positive 34% for HER2-positive breas
9、t cancer patients breast cancer patients breast cancer patients breast cancer patients ( Nature Review cancer, 2006, 6: 735-741) ( Nature Review cancer, 2006, 6: 735-741) ( Nature Review cancer, 2006, 6: 735-741) ( Nature Review cancer, 2006, 6: 735-741) Wood,LD,et.al(Science,2007,Nov.16,Vol.318:110
10、8) 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 in 24 additional tumors.Pathway rather than individu
11、al 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 alterations in a similar number of pathways.A few gene moun
12、tains 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 coding exons of 518 protein kinase genes in 210 diverse human canc
13、ers. 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 contributing to the development of the cancer studied in approxi
14、mately 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%) samples carried at least one mutationSian jones, et al, Scienceex
15、press, 2008, Sep. 4, 1-10 检查了24例胰腺癌的20661蛋白编码基因Pancreatic cancer contain an average of 63 genetic alterations, the majority of which are point mutations. These alterations defined a core set of 12 cellular signaling pathways 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 ex
16、ons of 20,857 transcript from 18,191gene. (Science,2007,Nov.16,Vol.318:1108) 2). Thomas RK,et al 分析分析17类肿瘤类肿瘤 238个个oncogenes 的突变的突变(Nature genetics, 2007: 39; 153-) 3). Greenman,C;et al. 分析分析210个不同人的肿瘤的个不同人的肿瘤的 518 protein kinase gene exons 的突变的突变 ( Nature, 2007, 446: 153-) The mutated genes in two
17、colorectal tumors overlap to only a small extentPathway 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 differences are likely to be the basis fo
18、r the wide variation in tumor behavior and responsiveness to therapythe acquisition of numerous somatic mutations, each with a small fitness advantage, may also drive tumourigenesis Molecular lesions that occur in early stage of cancer or in precursor lesions are more likely to have a direct influen
19、ce 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 . Next-generation sequencing CancerWhole Genome SequencingRecurring mutations found by sequencing an acute myeloid leukemia
20、genome. N Engl J Med. 2009 Sep 10;361(11):1058-66 38-year-old man of European ancestry DNA samples from the patients bone marrow sample and a normal skin- biopsy specimen obtained The AML genome that we sequenced contains approximately 750 point mutations, We identified 12 acquired (somatic) mutatio
21、ns within the coding sequences of genes and 52 somatic point mutations in conserved or regulatory portions in the tumor sample. Four of the 64 mutations occurred in at least 1 additional AML sample in 188 samples that were testedA comprehensive catalogue of somatic mutations from a human cancer geno
22、mePublished online 16 December 2009.Nature 08658 we have sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person We identified 33,345 somatic base substitutions. A total of 32,325 were single-base and 510 were double-base substitutionsA small-cell lung cance
23、r genome with complex signatures of tobacco exposure/nature Published online 16 December 2009. Using massively parallel sequencing technology, we sequenced a small-cell lung cancer cell line, NCI-H209, NCI-BL209 (an EpsteinBarr-virus-transformed lymphoblastoid line has been generated from the patien
24、t. ) to explore the mutational burden associated with tobacco smoking. A total of 22,910 somatic substitutions were identified, including 134 in coding exons. One mutation for every 15 cigarettes smoked. Cancer Molecular network disease caused by cellular abnormal growth and differentiation related
25、to developmental genomePNAS, 2007,104:8685-Gene Expression Profiles in Different Phases of Human Lung Embryonic Development and Tumorigenesis Development landscapeEmbudEarly FLMid FLAdult L(41k probes)DNA ReplicationDNA Replication Pre-InitiationDNA strand elongationE2F mediated regulation of DNA re
26、plicationE2F transcriptional targets at G1/SFOXM1 transcription factor networkFoxO family signalingG1/S TransitionG2/M CheckpointsG2/M DNA damage checkpointG2/M TransitionM PhaseM/G1 TransitionMitotic Metaphase/Anaphase TransitionMitotic PrometaphaseMitotic ProphaseMitotic Spindle CheckpointMitotic
27、Telophase /CytokinesisThe dynamic gene expressing patterns in human developmental process Clinical SignificanceThe expression level of these genes was correlated with survival cancer patients.Type of cancersAdenocarcinoma of the lung（242 samples)117, 125 samplesBrain Cancer（268 samples）Breast Cancer
28、（1077samples）249, 159, 179, 286 samplesP = 0.0407Survival analysis of 49 ADC patientsP = 0.041Overall survival analysis of 49 lung ADC patientsSurvival analysis of stage I lung ADC patients :the relationship between the development related genes and the prognosis of stage I lung ADC patients.Surviva
29、l analysis of 191 Glioma patientsP = 0.0299P = 0.0009Survival analysis of 80Glioma patientsSurvival analysis of glioma patients :The relationship between the development related genes and the overall survival of patients with glioma.The expression level of development related genes was associated wi
30、th the relapse-free survival of the breast cancer patients, which was confirmed in 7 independent datasets, involving 1300 samples.The expression level of development related genes was associated with the overall survival of the breast cancer patients, which was confirmed in 3 independent datasets.Th
31、e expression level of development related genes was associated with both the overall survival and the relapse-free survival of the breast cancer patients without lymph note metastasis (N0).For the patients treated with Tamoxifen, the expression level of the development related genes was associated w
32、ith their prognoses.The expression level of the development related genes was also associated with the prognoses of the patients not treated with Tamoxifen.The expression level of development related genes was associated with the Elston Histologic Grade of breast cancer.Most patients with Grade 1 br
33、east cancer (good prognosis) had a lower expression level of the development related genes. And most patients with Grade 3 (bad prognosis) had a higher expression level. However, the patients with Grade 2, whose prognosis was unpredictable according to Elston Histologic Grade, could still be divided
34、 into two groups with different expression level of development related genes. And the prognosis of the two groups of Elston Grade 2 patients was significantly different. Cancer prevention and treatment (present and future) High-risk individual-Precancerous lesions-invasive cancer Future present pre
35、vention (life style) Surgery Network drugs radiotherapy Vaccine chemotherapy new-therapy Key Steps for cancer research in the FutureTo intensify clinical investigation on human cancer and set up tumor tissue banks( translational study).To establish high-throughput platforms for fast analysis of genes, proteins, cell structures and functions through a synthetic approach.Systematic analysis of both clinical and basic research data with bioinformatics. Thank you
