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GENETICA DI TUMORI
INFANTILI E GIOVANILI
Lucio Luzzatto,
Scientific Director,
Istituto Toscano Tumori,
Firenze, ITALY
MARCO VENTURINI
in memoriam
Negrar, 12 maggio 2012
FORMATION OF A TUMOR RESULTS
FROM SOMATIC MUTATIONS AND DARWINIAN SELECTION
n-1
MUTATION
Normal tissue
Tumor
THE INCIDENCE
OF CANCER
DEPENDS STRONGLY
ON AGE
THE MOST COMMON TYPES OF CANCER IN YOUNG PEOPLE
Age 15-39
Under 15
____________________________
____________________________
• Acute lymphatic
leukemia (cALL)
• Medulloblastoma
• Glioma
• Neuroblastoma
• Wilms tumor
• Rhabdomyosarcoma
• Osteosarcoma
•
•
•
•
•
•
•
Lymphoma
Leukemia
Testicular
Melanoma
Glioma
Sarcomas
Other
p53:SOMATIC
MUTATIONS
versus
INHERITED MUTATIONS
BINDING TO CERTAIN SPECIFIC DNA ELEMENTS
IS CRUCIAL TO THE FUNCTIONS OF p53
Inherited mutants of p53 (Li-Fraumeni)
with differentially altered transcriptional functionality
cause different patterns of predisposition to cancer
PLF with all REs
100
p<0.0007
TLF with all REs
p<0.36
p<0.07
OLF
Tumor free individuals (%)
75
50
25
0
0
10
20
30
40
50
60
Age at diagnosis (yr)
(From Monti et al.,
Clinical Cancer Research 13:3789,2007)
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Other major initiatives accessible on line:
WELLCOME TRUST SANGER INSTITUTE CANCER GENOME PROJECT
http://www.sanger.ac.uk/research/projects/cancergenome/
NIH-NCI CANCER GENOME ANATOMY PROJECT
http://cgap.nci.nih.gov/
FEATURES OF HUMAN RETINOBLASTOMA
ARE RERMARKABLY CONSERVED
Original tumor
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Xenograft
from above
(From Zhang et al., Nature, 2012)
GENOMIC PROFILE OF RETINOBLASTOMA
IN TWO INDIVIDUAL PATIENTS
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From Zhang et al., Nature, 2012
RETINOBLASTOMA
HAS FEW MUTATIONS
WHEN COMPARED
TO OVARIAN CANCER
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From Zhang et al., Nature, 2012
TYPES OF MUTATIONS IN HUMAN CANCER
(From Futreal et al., 2004)
DISTRIBUTION OF NUMBER OF SOMATIC MUTATIONS
IN 65 CASES OF ‘TRIPLE NEGATIVE’ BREAST CANCER
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(From Shah et al, Nature 2012)
MOLECULAR CLASSIFICATION OF MEDULLOBLASTOMA
CORRELATES WITH CYTOGENETIC AND CLINICAL FEATURES
*
*
*
*
(From Kool et al., PLoS One 3:e3088,2008)
WNT AND SHH SUB-TYPES OF MEDULLOBLASTOMA
ARE ANATOMICALLY DISTINCT
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(From Gibson et al.,
Nature 468:1095,2010)
CHROMOTHRYPSIS IN MEDULLOBLASTOMA
IN LI-FRAUMENI PATIENTS
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(From Rausch et al., Cell 148:59,2012)
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144:9,2011
CHROMOTHRIPSIS 2011-2012
Seminal paper by P J Stephens et al.,
Cell 144: 27–40 (January 7), 2011.
Coined term and reported occurrence
in several types of tumors, including:
• Osteosarcoma
Then, confirmatory papers:
•
•
•
•
•
Neuroblastoma
Medulloblastoma
Prostate
Multiple myeloma
Colon
(~25%)
10
4
1
(~1.3%)
common
DETAILED ANALYSIS OF CHROMOTHRYPSIS
IN MEDULLOBLASTOMA IN LI-FRAUMENI PATIENTS
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(From Rausch et al., Cell 148:59,2012)
Maximum number
of copy number state changes
per chromosome
CORRELATION BETWEEN p53 STATUS AND CHROMOTRYPSIS
IN MEDULLOBLASTOMA
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Maximum amplicon count per chromosome
(From Rausch et al., Cell 148:59,2012)
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(From Rausch et al., Cell 148:59,2012)
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(From Demicco & Lazar,
Seminars in Oncology 38:S3-S18,2011)
Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 2
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(From Demicco & Lazar,
Seminars in Oncology 38:S3-S18,2011)
Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 3
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(From Demicco & Lazar,
Seminars in Oncology 38:S3-S18,2011)
Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 4
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(From Demicco & Lazar,
Seminars in Oncology 38:S3-S18,2011)
POINT MUTATIONS
AND
COPY NUMBER CHANGES
IN DIFFERENT TYPES
OF SOFT TISSUE SARCOMA
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(From Barretina et al.,
Nature Genetics
42:715,2010)
Depending on which protein domain is affected,
different mutations in the PIK3CA gene can produce markedly
different clinical course of soft tissue sarcoma.
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(From Barretina et al., Nature Genetics 42:715,2010)
PROTEINS INVOLVED IN THE t(X;18)
CHARACTERISTIC OF SYNOVIAL SARCOMA
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(From Haldar, Randall & Capecchi
Clin Orthop Relat Res 466:2156,2008)
STRATEGY TO PRODUCE IN THE MOUSE
A MODEL OF HUMAN SYNOVIAL SARCOMA
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(From Haldar, Randall & Capecchi
Clin Orthop Relat Res 466:2156,2008)
EXPRESSION OF THE SYT-SSX2 FUSION GENE
IN MYOBLASTS PRODUCES TUMORS THAT MIMIC
HUMAN SYNOVIAL SARCOMA
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(From Haldar, Randall & Capecchi
Clin Orthop Relat Res 466:2156,2008)
A MODEL FOR DEREPRESSION OF CADHERIN SYNTHESIS
MEDIATED BY SYT-SSX FUSIONS IN SYNOVIAL SARCOMA
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(From Saito et al., Cancer Research 66:6919,2006)
MODALITIES/EXTENT OF CADHERIN SYNTHESIS DEREPRESSION
IN SYNOVIAL SARCOMA DEPEND ON THE SYT PARTNER
IN SYT-SSX FUSIONS
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(From Saito et al., Cancer Research 66:6919,2006)
FORMATION OF A TUMOR RESULTS
FROM SOMATIC MUTATIONS AND DARWINIAN SELECTION
n-1
MUTATION
Normal tissue
Tumor
Process can be accelerated by:
- Increased rate of mutations
- Increased number of cell divisions
INHERITANCE
CHANCE
ENVIRONMENT
ONCOGENE ADDICTION
…The apparent dependency of some cancers
on one or a few genes for the maintenance
of the malignant phenotype
Bernard Weinstein
Clin Cancer Res 3:2696,1997
Science 297:63,2002
Cancer Res 68:3077,2008
MODEL OF ONCOGENE ADDICTION
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(From Torti & Trusolino EMBO Mol Med 3:623,2011)
Anti-angiogenici
Anti-infiammatori
Immunomodulatori
Farmaci che agiscono
sul DNA e sulla mitosi
(chemioterapici classici)
Inibitori
di un signal
transduction
pathway
importante in
un certo
tumore
(p.es. sunitinib)
Interferenza con molecole
mutate oncogeniche
(p.es. imatinib, gefitinib)
Interferenza
con molecola
iper-espressa
in un tumore
(p.es. trastuzumab)
TO UNDERSTAND,
TO TREAT
TO PREVENT CANCER
AT BEST FOR ALL