肿瘤防治的新挑战天津北方网权威媒体天津门户ppt课件

1、CancerMolecular Network DiseaseCheng shujun, Gao yanning, Medical Sciences, Peking Union Medical CollegeFortune Magazine, March 22,2019 Personalized Therapy progress and challenge Breast cancer patients with the same stage can have markedly different treatment responses. The clinical behaviour (such

2、 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 treatment, these patients may not benefit from the

3、 treatment, and may potentially suffer from the side effects. (Nature, 2019,VOl.415, 530) 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 outcome. Chemoth

4、erapy 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, 2019,VOl.415, 530)

5、FDA News FOR IMMEDIATE RELEASEP07-13February 6, 2019 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 the likelihood of tumor recu

6、rrence. Imatinib(Glivec) Chronic myelogenous leukemia(CML) Bcr-abl tyrosine kinase inhibitor . CML patients have high-expression of Bcr-abl fusion protein. Gefitinib (Iressa) (epidermal growth factor receptop tyrosine kinase inhibitor) Lung adenocarcinoma patients with relatively high frequency of E

7、GFR gene mutation Herceptin Breast cancer Her2 monoclonal antibody Ttumor regression 11-26% for unselected breast cancer patients, 34% for HER2-positive breast cancer patients ( Nature Review cancer, 2019, 6: 735-741) Wood,LD,et.al(Science,2019,Nov.16,Vol.318:1108) isolated DNA from 11 breast and 11

8、 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 individual genes appear to govern the course

9、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 mountains are mutated in a large proporti

10、on of tumors; most genes are mutated in 5% of tumors represented as hills两个肿瘤突变基因反复的很少， (Science 2019,318: 1108) Greenman,C et al(Nature, 2019,446:153-)reported 1,000 somatic mutations found in the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation

11、 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 approximately 120 genes.Thomas,RK et al.(Na

12、ture genetics,2019,39:347-)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, Scienceexpress, 2019, Sep. 4, 1-10 检查了24例胰腺癌的

13、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 DNA sequences based on exons of 20,857 transcript from 18,191gene. (S

14、cience,2019,Nov.16,Vol.318:1108) 2). Thomas RK,et al 分析17类肿瘤 238个oncogenes 的突变(Nature genetics, 2019: 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, 2019, 446: 153-) The mutated genes in two colorectal tumors overlap to only a small extentPathway rather tha

15、n 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 for the wide variation in tumor behavior and responsiveness to thera

16、pythe 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 influence on cancer occurrence and progression than those that accumulate

17、 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 genome. N Engl J Med. 2021 Sep 10;361(11):1058-66 38-year-old man

18、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) mutations within the coding sequences of genes and 52 somatic point mutat

19、ions 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 genomePublished online 16 December 2021.Nature 08658 we have sequenced

20、 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 cancer genome with complex signatures of tobacco exposure/nature Publis

21、hed online 16 December 2021. 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 patient. ) to explore the mutational burden associated with tobacco smok

22、ing. 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 to developmental genomePNAS, 2019,104:8685-Gene Expression Profile

23、s 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 replicationE2F transcriptional targets at G1/SFOXM1 transcription fa

24、ctor networkFoxO family signalingG1/S TransitionG2/M CheckpointsG2/M DNA damage checkpointG2/M TransitionM PhaseM/G1 TransitionMitotic Metaphase/Anaphase TransitionMitotic PrometaphaseMitotic ProphaseMitotic Spindle CheckpointMitotic Telophase /CytokinesisThe dynamic gene expressing patterns in huma

25、n developmental process Clinical Significance The expression level of these genes was correlated with survival cancer patients. Type of cancers Adenocarcinoma of the lung242 samples) 117, 125 samples Brain Cancer268 samples Breast Cancer1077samples 249, 159, 179, 286 samplesSurvival analysis01234567

26、1009080706050403020Time (years)Survival probability (%)Number at riskGroup: H25221583000Group: L242319146321SMC4_groupHLP=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 dev

27、elopment related genes and the prognosis of stage I lung ADC patients.events0246810100806040200TimeSurvival probability (%)Number at riskGroup: H100176000Group: L912513721Group_SHA_86HLSurvival analysis of 191 Glioma patientsP = 0.0299EVENTS01234567100908070605040302010TimeSurvival probability (%)Nu

28、mber at riskGroup: H4013643210Group: L40281896411SHA_86HLP = 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

29、 associated with 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 independe

30、nt datasets.The 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 wa

31、s associated with 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 breast cancer (good p