2. 2000
Figure 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. 2011
Figure 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
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

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. Colorectal Cancer
TUMOR
MUCOSA

14. Intratumor heterogeneity by double-sampling data
Mean of correlation coefficient in 18 double sampling pairs
Within pairs
0.75
Between pairs
0.19
0.8

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

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 cellule
tumorali

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

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

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

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

37. LEUCEMIA PROMIELOCITICA ACUTA

38. Role of transcription factors involved in promyelocytic acute leukemia
PML
RAR a
Apoptosis
Terminal myeloid
differentiation
(via p53 and/or Rb)
PML
RAR a
Oncogenesis