Genetica di tumori infantili e giovanili
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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.

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GENETICA DI TUMORI INFANTILI E GIOVANILI

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Genetica di tumori infantili e giovanili

GENETICA DI TUMORI INFANTILI E GIOVANILI

Lucio Luzzatto,

Scientific Director,

Istituto Toscano Tumori,

Firenze, ITALY

MARCO VENTURINI

in memoriam

Negrar, 12 maggio 2012


Genetica di tumori infantili e giovanili

FORMATION OF A TUMOR RESULTS

FROM SOMATIC MUTATIONS AND DARWINIAN SELECTION

n-1

MUTATION

Normal tissue

Tumor


Genetica di tumori infantili e giovanili

THE INCIDENCE

OF CANCER

DEPENDS STRONGLY

ON AGE


Genetica di tumori infantili e giovanili

Acute lymphatic leukemia (cALL)

Medulloblastoma

Glioma

Neuroblastoma

Wilms tumor

Rhabdomyosarcoma

Osteosarcoma

Lymphoma

Leukemia

Testicular

Melanoma

Glioma

Sarcomas

Other

THE MOST COMMON TYPES OF CANCER IN YOUNG PEOPLE

Age 15-39

Under 15

____________________________

____________________________


Genetica di tumori infantili e giovanili

p53:SOMATIC

MUTATIONS

versus

INHERITED MUTATIONS


Genetica di tumori infantili e giovanili

BINDING TO CERTAIN SPECIFIC DNA ELEMENTS

IS CRUCIAL TO THE FUNCTIONS OF p53


Genetica di tumori infantili e giovanili

PLF with all REs

p<0.0007

100

TLF with all REs

p<0.36

p<0.07

OLF

75

50

Tumor free individuals (%)

25

0

0

10

20

30

40

50

60

Age at diagnosis (yr)

Inherited mutants of p53 (Li-Fraumeni)

with differentially altered transcriptional functionality

cause different patterns of predisposition to cancer

(From Monti et al.,

ClinicalCancer Research13:3789,2007)


Genetica di tumori infantili e giovanili

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/


Genetica di tumori infantili e giovanili

FEATURES OF HUMAN RETINOBLASTOMA

ARE RERMARKABLY CONSERVED

Original tumor

Xenograft

from above

(From Zhang et al., Nature, 2012)


Genetica di tumori infantili e giovanili

GENOMIC PROFILE OF RETINOBLASTOMA

IN TWO INDIVIDUAL PATIENTS

From Zhang et al., Nature, 2012


Genetica di tumori infantili e giovanili

RETINOBLASTOMA

HAS FEW MUTATIONS

WHEN COMPARED

TO OVARIAN CANCER

From Zhang et al., Nature, 2012


Genetica di tumori infantili e giovanili

TYPES OF MUTATIONS IN HUMAN CANCER

(From Futreal et al., 2004)


Genetica di tumori infantili e giovanili

DISTRIBUTION OF NUMBER OF SOMATIC MUTATIONS

IN 65 CASES OF ‘TRIPLE NEGATIVE’ BREAST CANCER

(From Shah et al, Nature 2012)


Genetica di tumori infantili e giovanili

MOLECULAR CLASSIFICATION OF MEDULLOBLASTOMA

CORRELATES WITH CYTOGENETIC AND CLINICAL FEATURES

*

*

*

*

(From Kool et al., PLoS One3:e3088,2008)


Genetica di tumori infantili e giovanili

WNT AND SHH SUB-TYPES OF MEDULLOBLASTOMA

ARE ANATOMICALLY DISTINCT

(From Gibson et al.,

Nature468:1095,2010)


Genetica di tumori infantili e giovanili

CHROMOTHRYPSIS IN MEDULLOBLASTOMA

IN LI-FRAUMENI PATIENTS

(From Rausch et al., Cell148:59,2012)


Genetica di tumori infantili e giovanili

144:9,2011


Genetica di tumori infantili e giovanili

CHROMOTHRIPSIS 2011-2012

Seminal paper by P J Stephens et al.,

Cell144: 27–40 (January 7), 2011.

Coined term and reported occurrence

in several types of tumors, including:

  • Osteosarcoma (~25%)

  • Then, confirmatory papers:

  • Neuroblastoma 10

  • Medulloblastoma 4

  • Prostate 1

  • Multiple myeloma (~1.3%)

  • Colon common


Genetica di tumori infantili e giovanili

DETAILED ANALYSIS OF CHROMOTHRYPSIS

IN MEDULLOBLASTOMA IN LI-FRAUMENI PATIENTS

(From Rausch et al., Cell148:59,2012)


Genetica di tumori infantili e giovanili

Maximum number

of copy number state changes

per chromosome

Maximum amplicon count per chromosome

CORRELATION BETWEEN p53 STATUS AND CHROMOTRYPSIS

IN MEDULLOBLASTOMA

(From Rausch et al., Cell148:59,2012)


Genetica di tumori infantili e giovanili

(From Rausch et al., Cell148:59,2012)


Genetica di tumori infantili e giovanili

(From Demicco & Lazar,

Seminars in Oncology38:S3-S18,2011)


Genetica di tumori infantili e giovanili

Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 2

(From Demicco & Lazar,

Seminars in Oncology38:S3-S18,2011)


Genetica di tumori infantili e giovanili

Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 3

(From Demicco & Lazar,

Seminars in Oncology38:S3-S18,2011)


Genetica di tumori infantili e giovanili

Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 4

(From Demicco & Lazar,

Seminars in Oncology38:S3-S18,2011)


Genetica di tumori infantili e giovanili

POINT MUTATIONS

AND

COPY NUMBER CHANGES

IN DIFFERENT TYPES

OF SOFT TISSUE SARCOMA

(From Barretina et al.,

Nature Genetics

42:715,2010)


Genetica di tumori infantili e giovanili

Depending on which protein domain is affected,

different mutations in the PIK3CA gene can produce markedly different clinical course of soft tissue sarcoma.

(From Barretina et al., Nature Genetics42:715,2010)


Genetica di tumori infantili e giovanili

PROTEINS INVOLVED IN THE t(X;18)

CHARACTERISTIC OF SYNOVIAL SARCOMA

(From Haldar, Randall & Capecchi

Clin Orthop Relat Res466:2156,2008)


Genetica di tumori infantili e giovanili

STRATEGY TO PRODUCE IN THE MOUSE

A MODEL OF HUMAN SYNOVIAL SARCOMA

(From Haldar, Randall & Capecchi

Clin Orthop Relat Res466:2156,2008)


Genetica di tumori infantili e giovanili

EXPRESSION OF THE SYT-SSX2 FUSION GENE

IN MYOBLASTS PRODUCES TUMORS THAT MIMIC

HUMAN SYNOVIAL SARCOMA

(From Haldar, Randall & Capecchi

Clin Orthop Relat Res466:2156,2008)


Genetica di tumori infantili e giovanili

A MODEL FOR DEREPRESSION OF CADHERIN SYNTHESIS

MEDIATED BY SYT-SSX FUSIONS IN SYNOVIAL SARCOMA

(From Saito et al., Cancer Research66:6919,2006)


Genetica di tumori infantili e giovanili

MODALITIES/EXTENT OF CADHERIN SYNTHESIS DEREPRESSION IN SYNOVIAL SARCOMA DEPEND ON THE SYT PARTNER

IN SYT-SSX FUSIONS

(From Saito et al., Cancer Research66:6919,2006)


Genetica di tumori infantili e giovanili

n-1

MUTATION

Normal tissue

Tumor

FORMATION OF A TUMOR RESULTS

FROM SOMATIC MUTATIONS AND DARWINIAN SELECTION

Process can be accelerated by:

- Increased rate of mutations

- Increased number of cell divisions


Genetica di tumori infantili e giovanili

INHERITANCE

CHANCE

ENVIRONMENT


Genetica di tumori infantili e giovanili

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 Res3:2696,1997

Science297:63,2002

Cancer Res68:3077,2008


Genetica di tumori infantili e giovanili

MODEL OF ONCOGENE ADDICTION

(From Torti & Trusolino EMBO Mol Med3:623,2011)


Genetica di tumori infantili e giovanili

Farmaci che agiscono

sul DNA e sulla mitosi

(chemioterapici classici)

Anti-angiogenici

Anti-infiammatori

Immunomodulatori

Inibitori

di un signal transduction pathway

importante in un certo tumore

(p.es. sunitinib)

Interferenza

con molecola

iper-espressa

in un tumore

(p.es. trastuzumab)

Interferenza con molecole

mutate oncogeniche

(p.es. imatinib, gefitinib)


Genetica di tumori infantili e giovanili

TO UNDERSTAND,

TO TREAT

TO PREVENT CANCER

AT BEST FOR ALL

  • AOU Pisana

  • AUSL 5 Pisa

  • AUSL 6 Livorno - Ospedali Riuniti

  • AUSL 9 Grosseto


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