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

QuickTime™ and a decompressor

are needed to see this picture.

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:

QuickTime™ and a decompressor

are needed to see this picture.

(From Zhang et al., Nature, 2012)

FEATURES OF HUMAN RETINOBLASTOMA ARE RERMARKABLY CONSERVED

Original tumor

Xenograftfrom above

QuickTime™ and a decompressor

are needed to see this picture.

From Zhang et al., Nature, 2012

GENOMIC PROFILE OF RETINOBLASTOMAIN TWO INDIVIDUAL PATIENTS

QuickTime™ and a decompressor

are needed to see this picture.

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)

QuickTime™ and a decompressor

are needed to see this picture.

(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)

QuickTime™ and a decompressor

are needed to see this picture.

QuickTime™ and a decompressor

are needed to see this picture.

WNT AND SHH SUB-TYPES OF MEDULLOBLASTOMA ARE ANATOMICALLY DISTINCT

(From Gibson et al.,Nature 468:1095,2010)

QuickTime™ and a decompressor

are needed to see this picture.

(From Rausch et al., Cell 148:59,2012)

CHROMOTHRYPSIS IN MEDULLOBLASTOMA IN LI-FRAUMENI PATIENTS

QuickTime™ and a decompressor

are needed to see this picture.

QuickTime™ and a decompressor

are needed to see this picture.

144:9,2011

QuickTime™ and a decompressor

are needed to see this picture.

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:

QuickTime™ and a decompressor

are needed to see this picture.

(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)

QuickTime™ and a decompressor

are needed to see this picture.

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

QuickTime™ and a decompressor

are needed to see this picture.

(From Rausch et al., Cell 148:59,2012)

QuickTime™ and a decompressor

are needed to see this picture.

(From Demicco & Lazar,Seminars in Oncology 38:S3-S18,2011)

QuickTime™ and a decompressor

are needed to see this picture.

(From Demicco & Lazar,Seminars in Oncology 38:S3-S18,2011)

Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 2

QuickTime™ and a decompressor

are needed to see this picture.

(From Demicco & Lazar,Seminars in Oncology 38:S3-S18,2011)

Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 3

QuickTime™ and a decompressor

are needed to see this picture.

(From Demicco & Lazar,Seminars in Oncology 38:S3-S18,2011)

Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 4

QuickTime™ and a decompressor

are needed to see this picture.

(From Barretina et al., Nature Genetics

42:715,2010)

POINT MUTATIONSAND

COPY NUMBER CHANGESIN DIFFERENT TYPES

OF SOFT TISSUE SARCOMA

QuickTime™ and a decompressor

are needed to see this picture.

(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.

QuickTime™ and a decompressor

are needed to see this picture.

PROTEINS INVOLVED IN THE t(X;18) CHARACTERISTIC OF SYNOVIAL SARCOMA

(From Haldar, Randall & CapecchiClin Orthop Relat Res 466:2156,2008)

QuickTime™ and a decompressor

are needed to see this picture.

STRATEGY TO PRODUCE IN THE MOUSE A MODEL OF HUMAN SYNOVIAL SARCOMA

(From Haldar, Randall & CapecchiClin Orthop Relat Res 466:2156,2008)

QuickTime™ and a decompressor

are needed to see this picture.

(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

QuickTime™ and a decompressor

are needed to see this picture.

(From Saito et al., Cancer Research 66:6919,2006)

A MODEL FOR DEREPRESSION OF CADHERIN SYNTHESISMEDIATED BY SYT-SSX FUSIONS IN SYNOVIAL SARCOMA

QuickTime™ and a decompressor

are needed to see this picture.

(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

QuickTime™ and a decompressor

are needed to see this picture.

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