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
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 ____________________________ ____________________________
p53:SOMATIC MUTATIONS versus INHERITED MUTATIONS
BINDING TO CERTAIN SPECIFIC DNA ELEMENTS IS CRUCIAL TO THE FUNCTIONS OF p53
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)
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 Xenograft from above (From Zhang et al., Nature, 2012)
GENOMIC PROFILE OF RETINOBLASTOMA IN TWO INDIVIDUAL PATIENTS From Zhang et al., Nature, 2012
RETINOBLASTOMA HAS FEW MUTATIONS WHEN COMPARED TO OVARIAN CANCER 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 (From Shah et al, Nature 2012)
MOLECULAR CLASSIFICATION OF MEDULLOBLASTOMA CORRELATES WITH CYTOGENETIC AND CLINICAL FEATURES * * * * (From Kool et al., PLoS One3:e3088,2008)
WNT AND SHH SUB-TYPES OF MEDULLOBLASTOMA ARE ANATOMICALLY DISTINCT (From Gibson et al., Nature468:1095,2010)
CHROMOTHRYPSIS IN MEDULLOBLASTOMA IN LI-FRAUMENI PATIENTS (From Rausch et al., Cell148:59,2012)
144:9,2011
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
DETAILED ANALYSIS OF CHROMOTHRYPSIS IN MEDULLOBLASTOMA IN LI-FRAUMENI PATIENTS (From Rausch et al., Cell148:59,2012)
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)
(From Rausch et al., Cell148:59,2012)
(From Demicco & Lazar, Seminars in Oncology38:S3-S18,2011)
Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 2 (From Demicco & Lazar, Seminars in Oncology38:S3-S18,2011)
Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 3 (From Demicco & Lazar, Seminars in Oncology38:S3-S18,2011)
Chromosomal translocations/Amplifications in mesenchymal Neoplasms - 4 (From Demicco & Lazar, Seminars in Oncology38:S3-S18,2011)
POINT MUTATIONS AND COPY NUMBER CHANGES IN DIFFERENT TYPES OF SOFT TISSUE SARCOMA (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. (From Barretina et al., Nature Genetics42:715,2010)
PROTEINS INVOLVED IN THE t(X;18) CHARACTERISTIC OF SYNOVIAL SARCOMA (From Haldar, Randall & Capecchi Clin Orthop Relat Res466:2156,2008)
STRATEGY TO PRODUCE IN THE MOUSE A MODEL OF HUMAN SYNOVIAL SARCOMA (From Haldar, Randall & Capecchi Clin Orthop Relat Res466:2156,2008)
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)
A MODEL FOR DEREPRESSION OF CADHERIN SYNTHESIS MEDIATED BY SYT-SSX FUSIONS IN SYNOVIAL SARCOMA (From Saito et al., Cancer Research66:6919,2006)
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)
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
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 Res3:2696,1997 Science297:63,2002 Cancer Res68:3077,2008
MODEL OF ONCOGENE ADDICTION (From Torti & Trusolino EMBO Mol Med3:623,2011)
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)
TO UNDERSTAND, TO TREAT TO PREVENT CANCER AT BEST FOR ALL • AOU Pisana • AUSL 5 Pisa • AUSL 6 Livorno - Ospedali Riuniti • AUSL 9 Grosseto
