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Douglas Hanahan, Robert A. Weinberg Hallmarks of Cancer: The Next Generation Cell Volume 144, Issue 5 2011 646 - 674 2000.

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Presentation on theme: "Douglas Hanahan, Robert A. Weinberg Hallmarks of Cancer: The Next Generation Cell Volume 144, Issue 5 2011 646 - 674 2000."— Presentation transcript:

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2 Douglas Hanahan, Robert A. Weinberg Hallmarks of Cancer: The Next Generation Cell Volume 144, Issue

3 Douglas Hanahan, Robert A. Weinberg Hallmarks of Cancer: The Next Generation Cell Volume 144, Issue

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5 La cellula tumorale acquisisce queste caratteristiche mediante mutazioni alterazioni epigenetiche in un processo mutagenico multi-step

6 Mutazioni Mutazioni puntiformi Brevi inserzioni/delezioni CNA (copy number abnormalities): gain, loss, amplificazioni Aberrazioni cromosomiche bilanciate: traslocazioni, inversioni

7 Mutazioni di oncogeni: gain-of-function, amplificazione, e/o iperespressione Mutazioni di oncosoppressori: loss-of-function, delezione, e/o silenziamento epigenetico

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11 Teoria della selezione clonale

12 Eterogeneità clonale Più cloni (derivati da una unica cellula di origine del tumore, ma caratterizzati da eterogeneità genetica) possono coesistere contemporaneamente nella massa tumorale

13 TUMOR MUCOSA Colorectal Cancer

14 Intratumor heterogeneity by double-sampling data Mean of correlation coefficient in 18 double sampling pairs Within pairs0.75 Between pairs

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17 Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, USA. The Cancer Genome Atlas (TCGA) project was started in 2006 with the goal of collecting and profiling over 10,000 tumor samples from at least 20 tumor types. Half of these studies have been completed so far. The globally coordinated International Cancer Genome Consortium (ICGC), of which TCGA is a member, will add thousands more samples and additional tumor types

18 Selected Functional Events (SFEs). In total, we selected 479 candidate functional alterations, including 116 copy number gains, 151 copy number losses, 199 recurrently mutated genes and 13 epigenetically silenced genes.

19 The cancer genome hyperbola The distribution of SFEs in tumors indicates that the number of copy number alterations in a sample (x axis) is approximately anticorrelated with the number of somatic mutations in a sample (y axis).

20 The M class We identified 17 subclasses (M1–M17). These subclasses had alterations in distinct oncogenic pathways, with alterations of phosphatidylinositol 3-kinase (PI3K)-AKT signaling characterizing the first main subclass (M1– M8) and with APC, TP53 and KRAS mutations most prominent in the second subclass (M9–M14). The C class Overall hierarchical subdivision of the C class led to a first major partition into two groups, primarily determined by the absence (subclasses C1–C6) or presence (subclasses C7–C14) of gains and losses on chromosome 8. Inactivation of TP53, MYC-driven proliferation and dysregulated cell cycle checkpoints as the hallmarks of the C class of tumors, which is dominated by recurrent copy number changes

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23 We separated cases (84%) with a mutation rate of 12 per 10 6 (median number of total mutations 728), which we designated as hypermutated

24 Mutazioni driver che portano a variazioni funzionali importanti per il fenotipo tumorale Mutazioni passenger : neutrali, dovute allinstabilità del genoma delle cellule tumorali

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27 Overall, we identified 32 somatic recurrently mutated genes in the hypermutated and nonhypermutated cancers. After removal of non- expressed genes, there were 15 and 17 in the hypermutated and non-hypermutated cancers, respectively

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31 Janet Davison Rowley (born April 5, 1925) the first scientist to identify a chromosomal translocation as the cause of leukemia and other cancers.

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33 ABL Tyr BCR Autophosphorylation by dimerization P Phosphorylation of substrates The constitutive TK activity of BCR-ABL is the primary factor causing the expansion of the Ph-positive clone

34 NUCLEUS Cell Cycle BCR/ABL Paxillin F-actin 2. Changes in adhesion to stromal layer General overview 3- Inhibition of apoptosis PIK3 -AKT RAS JAK-STAT 1. Activation of proliferation MYC

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37 LEUCEMIA PROMIELOCITICA ACUTA

38 Role of transcription factors involved in promyelocytic acute leukemia ApoptosisTerminal myeloid differentiation Oncogenesis (via p53 and/or Rb)


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