Presentation on theme: "2000 Figure 1 The Hallmarks of Cancer This illustration encompasses the six hallmark capabilities originally proposed in our 2000 perspective. The past."— Presentation transcript:
2 2000Figure 1 The Hallmarks of Cancer This illustration encompasses the six hallmark capabilities originally proposed in our 2000 perspective. The past decade has witnessed remarkable progress toward understanding the mechanistic underpinnings of each hallmark...Douglas Hanahan , Robert A. Weinberg Hallmarks of Cancer: The Next Generation Cell Volume 144, Issue
3 2011Figure 3 Emerging Hallmarks and Enabling Characteristics An increasing body of research suggests that two additional hallmarks of cancer are involved in the pathogenesis of some and perhaps all cancers. One involves the capability to modify, or reprogram,...Douglas Hanahan , Robert A. Weinberg Hallmarks of Cancer: The Next Generation Cell Volume 144, Issue
4 Figure 6 Therapeutic Targeting of the Hallmarks of Cancer Drugs that interfere with each of the acquired capabilities necessary for tumor growth and progression have been developed and are in clinical trials or in some cases approved for clinical use in t...
5 La cellula tumorale acquisisce queste caratteristiche mediante mutazionialterazioni epigenetichein un processo mutagenicomulti-step
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 classWe 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 classOverall 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
23 We separated cases (84%) with a mutation rate of < 8 We separated cases (84%) with a mutation rate of < 8.24 per 106 and those with mutation rates of >12 per 106 (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 all’instabilità del genoma delle celluletumorali
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
33 The constitutive TK activity of BCR-ABL is the primary factor causing the expansionof the Ph-positive cloneAutophosphorylationby dimerizationABL ABLTyr TyrBCR BCRPhosphorylationof substratesP
34 1. Activation of proliferation General overviewRASJAK-STAT1. Activation of proliferationMYCBCR/ABLPaxillinF-actin2. Changes in adhesionto stromal layerNUCLEUS3- Inhibition ofapoptosisPIK3 -AKTCell Cycle