Presentation on theme: "Prospettive sul tumore della mammella: nuove osservazioni, quali opportunità? Cremona, 24 maggio 2008 Paolo Radice P53 E TUMORE MAMMARIO ISTITUTO NAZIONALE."— Presentation transcript:
1 Prospettive sul tumore della mammella: nuove osservazioni, quali opportunità? Cremona, 24 maggio 2008Paolo RadiceP53 E TUMORE MAMMARIOISTITUTO NAZIONALEPER LO STUDIO E LACURA DEI TUMORIISTITUTO FIRCDI ONCOLOGIAMOLECOLAREMilan, Italy
2 Familial breast cancer cases high-penetrance genes: BRCA1 and BRCA2“less-penetrant” genes: TP53, PTEN, LKB1, ATM, CHEK2, BRIP1, PALB2 and other to be identified20 %5 %genetics factors are the most plausible explanations and briefly the reasons are these:75 %other genetic factors?
5 Li Fraumeni Syndrome1969 Li and Fraumeni reviewed FH of 648 children withRMS and identified5 families with another case of sarcoma1982 Update follow-up of 4 families and description ofan unusual familial clustering of cancers:- sarcomas- breast cancers- early-onset carcinomas- brain tumors
6 Diagnostic criteria for LFS and LFL Li-Fraumeni syndrome (Li et al., Cancer Res 1988)Proband <45 years with a sarcomaplus 1st degree relative <45 years with any cancerplus additional 1st or 2nd degree relative in the same lineage aged <45 years with any cancer or a sarcoma at any ageLi-Fraumeni syndrome (Birch et al., Cancer Res 1994)Proband with any childhood tumour, or sarcoma, brain tumour, or adrenocortical tumour <45 yearsplus additional 1st or 2nd degree relative in the same lineage with typical LFS tumour at any age or any cancer <45 yearsplus another additional 1st or 2nd degree relative in the same lineage with any cancer <60 years
7 Li Fraumeni Syndrome1969 Li and Fraumeni reviewed FH of 648 children with RMS and identified5 families with another case of sarcoma1982 Update follow-up of 4 families and description ofan unusual familial clustering of cancers:- sarcomas- breast cancers- early-onset carcinomas- brain tumors1990 Malkin et al. identify p53 germline mutations in5 LFS families
8 Tumour specrtum in families TP53 germline mutations **prostate, pancreatic, bladder, hepatocellular, naso-pharyngeal and laryngeal ca, Wilms tumour, hepatoblastoma, melanoma, teratoma, neuroblastomaOlivier et al., Cancer Res 2003
9 Age distributions of the major tumour sites in TP53 mutation carriers Olivier et al.,Cancer Res 2003Age at onset
10 Multiple primary tumours in LFS 15 % developed a 2nd cancer (interval 1-27 years)relative risk is higher if 1st tumor diagnosed in infancy4 % developed a 3rd cancer2 % developed a 4th canceramong patient who developed a 2nd tumor a consistent fractionhad received previous radiotherapy (interval 3-22 years, tumors in RT field)
11 IVS3 –11C>G (skipping of exon 4) A LFS family pedigreeleiomiosarcoma 15 aacarcinoma mammella dx 25 aacarcinoma mammella sx 27 aacarcinoma corteccia surrenale 27 aaTP53 gene mutationIVS3 –11C>G (skipping of exon 4)INT - Milano
12 Genotype-phenotype correlations in LFS TP53 mutations are detectable in 50-70% of LFS families, but only in 20% of LFL families (Varley et al., Br J Cancer 1997)MutationsTumoursMissense mutatios in the DNA binding domainsBrain tumoursMissense mutations outside DNA binding domainsAdrenal tumours‘Null’ mutationsBrain tumours (early onset)(Olivier et al., Cancer Res 2003)
13 Mutation screenings in Hereditary Breast Cancer* *as of April 2008Mutation positivesMutation negativesINTBRCA1/ TP53Mutation detection rates % %
14 Germline mutations of TP53 and BRCA2 genes in breast cancer/sarcoma families (Manoukian et al. Eur J cancer, 2007)AIMTo verify the involvement of BRCA1 and BRCA2 genes in breast cancer/sarcoma families unlinked to TP53.INT
15 CASE MATERIAL23 families with one case of sarcoma and one or more cases of breast carcinoma.Family classificationLFSLFLnon-LFS/non-LFLTotalHBOC251320non-HBOC31623INT
16 Diagnostic criteria for HBOC Three or more first degree relatives* affected with breast cancer or ovarian cancer at any ageTwo first degree relatives* affected with :breast cancer < 50 yearsbreast cancer < 50 years plus breast cancer bilateral at any agebreast cancer < 50 years plus ovarian cancer at any agebreast cancer < 50 yrs plus male breast cancer at any ageovarian cancer at any age*or second degree relatives if in paternal lineageINT
17 RESULTS INT Germline mutations HBOC non-HBOC Total LFS LFL non-LFS/non-LFLTP5312*3*BRCA1BRCA2None identified2123185*1323**one case carried both a TP53 and BRCA2 mutationsINT
19 CONCLUSIONSThe screening of BRCA2, in addition to TP53, may be appropriate for the molecular characterisation of breast cancer/sarcoma families, with practical implications for counselling and clinical management.Although we could not provide evidence that BRCA2 mutations are associated with an increased risk of sarcoma, our results indicate that the presence of these malignancies in HBOC families is not a negative predictor of mutations of BRCA2.The role of BRCA1 in breast/sarcoma families remains undeterminedINT
20 FONDAZIONE IRCCS ISTITUTO NAZIONALE TUMORI (INT), MILANO Siranoush ManoukianBernard PeisselSilvia StacchiottiMonica TerenzianiGraziella PasquiniSimona FrigerioMarco A. PierottiGabriella Della TorreFONDAZIONE ISTiTUTO FIRC DI ONCOOGIA mOLECOLARE (IFOM), MILANOValeria PensottiFloriana BarberaISTITUTO EUROPEO DI ONOCLOGIAMonica BarileUNIVERSITA’ DI MODENA E REGGIO EMILIALaura Cortesi
21 Follow-up in LFS avoid RX, MX, TC ?? avoid environmental carcinogens healthy life stilebe alert for early signs of cancerannual clinical examinationabdomen ultrasound < age 16breast clinical examination every 6 months + MRI / breast US > 25 yrsannual brain MRIgastroscopy, Hemoccultblood cell counts ?
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