genetica di tumori infantili e giovanili lucio luzzatto, scientific director, istituto toscano...
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GENETICA DI TUMORI INFANTILI E GIOVANILI
Lucio Luzzatto, Scientific Director,
Istituto Toscano Tumori,Firenze, ITALY
MARCO VENTURINIin memoriam
Negrar, 12 maggio 2012
MUTATION
Normal tissue
Tumor
n-1
FORMATION OF A TUMOR RESULTSFROM SOMATIC MUTATIONS AND DARWINIAN SELECTION
THE INCIDENCE OF CANCERDEPENDS STRONGLYON AGE
THE MOST COMMON TYPES OF CANCER IN YOUNG PEOPLE
• Acute lymphatic leukemia (cALL)
• Medulloblastoma• Glioma• Neuroblastoma• Wilms tumor• Rhabdomyosarcoma• Osteosarcoma
• Lymphoma• Leukemia• Testicular• Melanoma• Glioma• Sarcomas• Other
Under 15 Age 15-39____________________________ ____________________________
p53:SOMATIC MUTATIONS versus INHERITED MUTATIONS
BINDING TO CERTAIN SPECIFIC DNA ELEMENTS IS CRUCIAL TO THE FUNCTIONS OF p53
0 10 20 30 40 50 600
25
50
75
100PLF with all REs
TLF with all REs
OLF
p<0.0007p<0.36
p<0.07
Age at diagnosis (yr)
Tu
mor
fre
e in
div
idu
als
(%)
(From Monti et al.,Clinical Cancer Research 13:3789,2007)
Inherited mutants of p53 (Li-Fraumeni) with differentially altered transcriptional functionality
cause different patterns of predisposition to cancer
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WELLCOME TRUST SANGER INSTITUTE CANCER GENOME PROJECThttp://www.sanger.ac.uk/research/projects/cancergenome/
NIH-NCI CANCER GENOME ANATOMY PROJECThttp://cgap.nci.nih.gov/
Other major initiatives accessible on line:
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(From Zhang et al., Nature, 2012)
FEATURES OF HUMAN RETINOBLASTOMA ARE RERMARKABLY CONSERVED
Original tumor
Xenograftfrom above
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From Zhang et al., Nature, 2012
GENOMIC PROFILE OF RETINOBLASTOMAIN TWO INDIVIDUAL PATIENTS
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From Zhang et al., Nature, 2012
RETINOBLASTOMA HAS FEW MUTATIONS
WHEN COMPARED TO OVARIAN CANCER
TYPES OF MUTATIONS IN HUMAN CANCER
(From Futreal et al., 2004)
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(From Shah et al, Nature 2012)
DISTRIBUTION OF NUMBER OF SOMATIC MUTATIONSIN 65 CASES OF ‘TRIPLE NEGATIVE’ BREAST CANCER
* *
**
MOLECULAR CLASSIFICATION OF MEDULLOBLASTOMACORRELATES WITH CYTOGENETIC AND CLINICAL FEATURES
(From Kool et al., PLoS One 3:e3088,2008)
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WNT AND SHH SUB-TYPES OF MEDULLOBLASTOMA ARE ANATOMICALLY DISTINCT
(From Gibson et al.,Nature 468:1095,2010)
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(From Rausch et al., Cell 148:59,2012)
CHROMOTHRYPSIS IN MEDULLOBLASTOMA IN LI-FRAUMENI PATIENTS
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144:9,2011
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CHROMOTHRIPSIS 2011-2012
• Osteosarcoma (~25%)Then, confirmatory papers:• Neuroblastoma 10• Medulloblastoma 4• Prostate 1• Multiple myeloma (~1.3%) • Colon common
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:
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(From Rausch et al., Cell 148:59,2012)
DETAILED ANALYSIS OF CHROMOTHRYPSIS IN MEDULLOBLASTOMA IN LI-FRAUMENI PATIENTS
(From Rausch et al., Cell 148:59,2012)
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Maximum amplicon count per chromosome
Max
imum
num
ber
of c
opy
num
ber
stat
e ch
ange
spe
r ch
rom
osom
e
CORRELATION BETWEEN p53 STATUS AND CHROMOTRYPSISIN MEDULLOBLASTOMA
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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)
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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 Barretina et al., Nature Genetics
42:715,2010)
POINT MUTATIONSAND
COPY NUMBER CHANGESIN 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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PROTEINS INVOLVED IN THE t(X;18) CHARACTERISTIC OF SYNOVIAL SARCOMA
(From Haldar, Randall & CapecchiClin Orthop Relat Res 466:2156,2008)
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STRATEGY TO PRODUCE IN THE MOUSE A MODEL OF HUMAN SYNOVIAL SARCOMA
(From Haldar, Randall & CapecchiClin Orthop Relat Res 466:2156,2008)
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(From Haldar, Randall & CapecchiClin Orthop Relat Res 466:2156,2008)
EXPRESSION OF THE SYT-SSX2 FUSION GENEIN MYOBLASTS PRODUCES TUMORS THAT MIMIC
HUMAN SYNOVIAL SARCOMA
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(From Saito et al., Cancer Research 66:6919,2006)
A MODEL FOR DEREPRESSION OF CADHERIN SYNTHESISMEDIATED 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
MUTATION
Normal tissueTumor
n-1
FORMATION OF A TUMOR RESULTSFROM SOMATIC MUTATIONS AND DARWINIAN SELECTION
Process can be accelerated by:- Increased rate of mutations- Increased number of cell divisions
CHANCE
ENVIRONMENT
INHERITANCE
ONCOGENE ADDICTION
…The apparent dependency of some cancers on one or a few genes for the maintenanceof the malignant phenotype
Bernard Weinstein
Clin Cancer Res 3:2696,1997Science 297:63,2002
Cancer Res 68:3077,2008
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MODEL OF ONCOGENE ADDICTION
(From Torti & Trusolino EMBO Mol Med 3:623,2011)
Anti-angiogeniciAnti-infiammatoriImmunomodulatori
Interferenza con molecolaiper-espressa in un tumore(p.es. trastuzumab)
Farmaci che agisconosul DNA e sulla mitosi(chemioterapici classici)
Inibitori di un signal transduction pathwayimportante in un certo tumore(p.es. sunitinib)
Interferenza con molecolemutate oncogeniche(p.es. imatinib, gefitinib)
TO UNDERSTAND,TO TREAT
TO PREVENT CANCERAT BEST FOR ALL