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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

GENETICA DI TUMORI INFANTILI E GIOVANILI

Lucio Luzzatto,

Scientific Director,

Istituto Toscano Tumori,

Firenze, ITALY

MARCO VENTURINI

in memoriam

Negrar, 12 maggio 2012

slide2

FORMATION OF A TUMOR RESULTS

FROM SOMATIC MUTATIONS AND DARWINIAN SELECTION

n-1

MUTATION

Normal tissue

Tumor

slide3

THE INCIDENCE

OF CANCER

DEPENDS STRONGLY

ON AGE

slide4
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

____________________________

____________________________

slide5

p53:SOMATIC

MUTATIONS

versus

INHERITED MUTATIONS

slide6

BINDING TO CERTAIN SPECIFIC DNA ELEMENTS

IS CRUCIAL TO THE FUNCTIONS OF p53

slide8

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)

slide9

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/

slide10

FEATURES OF HUMAN RETINOBLASTOMA

ARE RERMARKABLY CONSERVED

Original tumor

Xenograft

from above

(From Zhang et al., Nature, 2012)

slide11

GENOMIC PROFILE OF RETINOBLASTOMA

IN TWO INDIVIDUAL PATIENTS

From Zhang et al., Nature, 2012

slide12

RETINOBLASTOMA

HAS FEW MUTATIONS

WHEN COMPARED

TO OVARIAN CANCER

From Zhang et al., Nature, 2012

slide13

TYPES OF MUTATIONS IN HUMAN CANCER

(From Futreal et al., 2004)

slide14

DISTRIBUTION OF NUMBER OF SOMATIC MUTATIONS

IN 65 CASES OF ‘TRIPLE NEGATIVE’ BREAST CANCER

(From Shah et al, Nature 2012)

slide15

MOLECULAR CLASSIFICATION OF MEDULLOBLASTOMA

CORRELATES WITH CYTOGENETIC AND CLINICAL FEATURES

*

*

*

*

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

slide16

WNT AND SHH SUB-TYPES OF MEDULLOBLASTOMA

ARE ANATOMICALLY DISTINCT

(From Gibson et al.,

Nature468:1095,2010)

slide17

CHROMOTHRYPSIS IN MEDULLOBLASTOMA

IN LI-FRAUMENI PATIENTS

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

slide19

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
slide20

DETAILED ANALYSIS OF CHROMOTHRYPSIS

IN MEDULLOBLASTOMA IN LI-FRAUMENI PATIENTS

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

slide21

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)

slide23

(From Demicco & Lazar,

Seminars in Oncology38:S3-S18,2011)

slide24

Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 2

(From Demicco & Lazar,

Seminars in Oncology38:S3-S18,2011)

slide25

Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 3

(From Demicco & Lazar,

Seminars in Oncology38:S3-S18,2011)

slide26

Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 4

(From Demicco & Lazar,

Seminars in Oncology38:S3-S18,2011)

slide27

POINT MUTATIONS

AND

COPY NUMBER CHANGES

IN DIFFERENT TYPES

OF SOFT TISSUE SARCOMA

(From Barretina et al.,

Nature Genetics

42:715,2010)

slide28

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)

slide29

PROTEINS INVOLVED IN THE t(X;18)

CHARACTERISTIC OF SYNOVIAL SARCOMA

(From Haldar, Randall & Capecchi

Clin Orthop Relat Res466:2156,2008)

slide30

STRATEGY TO PRODUCE IN THE MOUSE

A MODEL OF HUMAN SYNOVIAL SARCOMA

(From Haldar, Randall & Capecchi

Clin Orthop Relat Res466:2156,2008)

slide31

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)

slide32

A MODEL FOR DEREPRESSION OF CADHERIN SYNTHESIS

MEDIATED BY SYT-SSX FUSIONS IN SYNOVIAL SARCOMA

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

slide33

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)

slide34

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

slide35

INHERITANCE

CHANCE

ENVIRONMENT

slide36

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

slide37

MODEL OF ONCOGENE ADDICTION

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

slide38

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)

slide39

TO UNDERSTAND,

TO TREAT

TO PREVENT CANCER

AT BEST FOR ALL

  • AOU Pisana
  • AUSL 5 Pisa
  • AUSL 6 Livorno - Ospedali Riuniti
  • AUSL 9 Grosseto