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P53 E TUMORE MAMMARIO Paolo Radice ISTITUTO NAZIONALE PER LO STUDIO E LA CURA DEI TUMORI ISTITUTO FIRC DI ONCOLOGIA MOLECOLARE Milan, Italy Prospettive.

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Presentation on theme: "P53 E TUMORE MAMMARIO Paolo Radice ISTITUTO NAZIONALE PER LO STUDIO E LA CURA DEI TUMORI ISTITUTO FIRC DI ONCOLOGIA MOLECOLARE Milan, Italy Prospettive."— Presentation transcript:

1 P53 E TUMORE MAMMARIO Paolo Radice ISTITUTO NAZIONALE PER LO STUDIO E LA CURA DEI TUMORI ISTITUTO FIRC DI ONCOLOGIA MOLECOLARE Milan, Italy Prospettive sul tumore della mammella: nuove osservazioni, quali opportunità? Cremona, 24 maggio 2008

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 identified other genetic factors? 20 % 5 % 75 %

3

4 the p53 protein

5 Li Fraumeni Syndrome 1969 Li and Fraumeni reviewed FH of 648 children with RMS and identified 5 families with another case of sarcoma 1982Update follow-up of 4 families and description of an 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) Li-Fraumeni syndrome (Li et al., Cancer Res 1988) Proband <45 years with a sarcomaProband <45 years with a sarcoma plus 1st degree relative <45 years with any cancerplus 1st degree relative <45 years with any cancer plus additional 1st or 2nd degree relative in the same lineage aged <45 years with any cancer or a sarcoma at any ageplus additional 1st or 2nd degree relative in the same lineage aged <45 years with any cancer or a sarcoma at any age Li-Fraumeni syndrome (Birch et al., Cancer Res 1994) Li-Fraumeni syndrome (Birch et al., Cancer Res 1994) Proband with any childhood tumour, or sarcoma, brain tumour, or adrenocortical tumour <45 yearsProband with any childhood tumour, or sarcoma, brain tumour, or adrenocortical tumour <45 years plus additional 1st or 2nd degree relative in the same lineage with typical LFS tumour at any age or any cancer <45 yearsplus additional 1st or 2nd degree relative in the same lineage with typical LFS tumour at any age or any cancer <45 years plus another additional 1st or 2nd degree relative in the same lineage with any cancer <60 yearsplus another additional 1st or 2nd degree relative in the same lineage with any cancer <60 years

7 Li Fraumeni Syndrome 1969 Li and Fraumeni reviewed FH of 648 children with RMS and identified 5 families with another case of sarcoma Update follow-up of 4 families and description of an unusual familial clustering of cancers: - sarcomas -breast cancers -early-onset carcinomas -brain tumors Malkin et al. identify p53 germline mutations in 5 LFS families

8 Tumour specrtum in families TP53 germline mutations * *prostate, pancreatic, bladder, hepatocellular, naso-pharyngeal and laryngeal ca, Wilms tumour, hepatoblastoma, melanoma, teratoma, neuroblastoma Olivier et al., Cancer Res 2003

9 Age at onset Age distributions of the major tumour sites in TP53 mutation carriers Olivier et al., Cancer Res 2003

10 Multiple primary tumours in LFS 15 %developed a 2 nd cancer (interval 1-27 years) 15 %developed a 2 nd cancer (interval 1-27 years) relative risk is higher if 1 st tumor diagnosed in infancy 4 %developed a 3 rd cancer 4 %developed a 3 rd cancer 2 %developed a 4 th cancer 2 %developed a 4 th cancer among patient who developed a 2 nd tumor a consistent fraction had received previous radiotherapy (interval 3-22 years, tumors in RT field)

11 A LFS family pedigree leiomiosarcoma 15 aa carcinoma mammella dx 25 aa carcinoma mammella sx 27 aa carcinoma corteccia surrenale 27 aa TP53 gene mutation IVS3 –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) TP53 mutations are detectable in 50-70% of LFS families, but only in 20% of LFL families (Varley et al., Br J Cancer 1997) MutationsTumours Missense mutatios in the DNA binding domains Brain tumours Missense mutations outside DNA binding domains Adrenal tumours Null mutations Brain tumours (early onset) (Olivier et al., Cancer Res 2003)

13 Mutation screenings in Hereditary Breast Cancer* BRCA1/2 TP53 Mutation detection rates 30% 13% *as of April 2008 INT Mutation positives Mutation negatives

14 Germline mutations of TP53 and BRCA2 genes in breast cancer/sarcoma families (Manoukian et al. Eur J cancer, 2007) INT AIM To verify the involvement of BRCA1 and BRCA2 genes in breast cancer/sarcoma families unlinked to TP53.

15 CASE MATERIAL 23 families with one case of sarcoma and one or more cases of breast carcinoma. 23 families with one case of sarcoma and one or more cases of breast carcinoma. INT Family classificationLFSLFLnon-LFS/non-LFLTotal HBOC non-HBOC0033 Total251623

16 Diagnostic criteria for HBOC Three or more first degree relatives* affected with breast cancer or ovarian cancer at any ageThree or more first degree relatives* affected with breast cancer or ovarian cancer at any age Two first degree relatives* affected with :Two first degree relatives* affected with : breast cancer < 50 yearsbreast cancer < 50 years breast cancer < 50 years plus breast cancer bilateral at any agebreast cancer < 50 years plus breast cancer bilateral at any age breast cancer < 50 years plus ovarian cancer at any agebreast cancer < 50 years plus ovarian cancer at any age breast cancer < 50 yrs plus male breast cancer at any agebreast cancer < 50 yrs plus male breast cancer at any age ovarian cancer at any ageovarian cancer at any age *or second degree relatives if in paternal lineage INT

17 RESULTS Germline mutations HBOC non-HBOCTotal LFSLFLnon-LFS/non-LFL TP5312*003* BRCA BRCA202*103* None identified Total25*13323* *one case carried both a TP53 and BRCA2 mutations

18 * Family no. 7

19 CONCLUSIONS The 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. The 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. INT 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. 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 undetermined The role of BRCA1 in breast/sarcoma families remains undetermined

20 FONDAZIONE IRCCS ISTITUTO NAZIONALE TUMORI (INT), MILANO Siranoush Manoukian Bernard Peissel Silvia Stacchiotti Monica Terenziani Graziella Pasquini Simona Frigerio Marco A. Pierotti Gabriella Della Torre FONDAZIONE ISTiTUTO FIRC DI ONCOOGIA mOLECOLARE (IFOM), MILANO Valeria Pensotti Floriana Barbera ISTITUTO EUROPEO DI ONOCLOGIA Monica Barile UNIVERSITA DI MODENA E REGGIO EMILIA Laura Cortesi

21 Follow-up in LFS avoid RX, MX, TC ?? avoid RX, MX, TC ?? avoid environmental carcinogens avoid environmental carcinogens healthy life stile healthy life stile be alert for early signs of cancer be alert for early signs of cancer annual clinical examination annual clinical examination abdomen ultrasound < age 16 abdomen ultrasound < age 16 breast clinical examination every 6 months + MRI / breast US > 25 yrs breast clinical examination every 6 months + MRI / breast US > 25 yrs annual brain MRI annual brain MRI gastroscopy, Hemoccult gastroscopy, Hemoccult blood cell counts ? blood cell counts ?


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