2000
Douglas Hanahan , Robert A. Weinberg
Hallmarks of Cancer:
The Next Generation Cell Volume 144, Issue 5 2011 646 - 674
2011
Douglas Hanahan , Robert A. Weinberg
Hallmarks of Cancer:
The Next Generation Cell Volume 144, Issue 5 2011 646 - 674
La cellula tumorale acquisisce
queste caratteristiche mediante
• mutazioni
• alterazioni epigenetiche
in un processo mutagenico
multi-step
Mutazioni
Mutazioni puntiformi
Brevi inserzioni/delezioni
CNA (copy number abnormalities):
gain, loss, amplificazioni
Aberrazioni cromosomiche bilanciate:
traslocazioni, inversioni
Mutazioni di oncogeni:
gain-of-function, amplificazione, e/o
iperespressione
Mutazioni di oncosoppressori:
loss-of-function, delezione, e/o silenziamento
epigenetico
Teoria della selezione clonale
Eterogeneità clonale
Più cloni (derivati da una unica cellula di
origine del tumore, ma caratterizzati da
eterogeneità genetica) possono coesistere
contemporaneamente nella massa tumorale
Colorectal Cancer
TUMOR
MUCOSA
Intratumor heterogeneity by
double-sampling data
Mean of correlation coefficient
in 18 double sampling pairs
0.8
Within pairs
0.75
Between pairs
0.19
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
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).
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
Mutazioni “driver” che portano a variazioni
funzionali importanti per il fenotipo tumorale
Mutazioni “passenger” : neutrali, dovute
all’instabilità del genoma delle cellule
tumorali
Overall, we identified 32 somatic recurrently mutated genes in the
hypermutated and nonhypermutated cancers. After removal of nonexpressed genes, there were 15 and 17 in the hypermutated and
non-hypermutated cancers, respectively
Leucemia Mieloide Cronica (LMC)
Il cromosoma Philadelphia:
l’anomalia citogenetica responsabile della malattia
1
6
2
7
13
14
19
20
3
8
4
9
15
21
10
16
22
Dimostrabile nel 95%dei pazienti affetti da LMC
5
11
12
17
18
x
Y
Janet Davison Rowley (born April 5,
1925) the first scientist to identify a
chromosomal translocation as the
cause of leukemia and other cancers.
Formazione del cromosoma Philadelphia(Ph)
La traslocazione t (9;22)
Cromosoma
Cromosoma
9
9+
Cromosoma
Cromosoma
22
Ph
bcr
Bcr-Abl
abl
Proteina di fusione
con attività
tirosina-chinasica
leucemogenica
The constitutive TK activity of BCR-ABL is
the primary factor causing the expansion
of the Ph-positive clone
Autophosphorylation
by dimerization
BCR
ABL
BCR
Phosphorylation
of substrates
ABL
P
Tyr
Tyr
General overview
RAS
JAK-STAT
BCR/ABL
MYC
1. Activation of proliferation
F-actin
Paxillin
PIK3 -AKT
2. Changes in adhesion
to stromal layer
3- Inhibition
of
apoptosis
NUCLEUS
Cell Cycle
LEUCEMIA PROMIELOCITICA ACUTA
Role of transcription factors involved in
promyelocytic acute leukemia
Apoptosis
(via p53 and/or Rb)
Terminal myeloid
differentiation
Oncogenesis