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

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 20 % 5 % genetics factors are the most plausible explanations and briefly the reasons are these: 75 % other genetic factors?

http://p53.free.fr/index.html

http://p53.free.fr/index.html the p53 protein

Li Fraumeni Syndrome 1969 Li and Fraumeni reviewed FH of 648 children with RMS and identified 5 families with another case of sarcoma 1982 Update follow-up of 4 families and description of an unusual familial clustering of cancers: - sarcomas - breast cancers - early-onset carcinomas - brain tumors

Diagnostic criteria for LFS and LFL Li-Fraumeni syndrome (Li et al., Cancer Res 1988) Proband <45 years with a sarcoma plus 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 age Li-Fraumeni syndrome (Birch et al., Cancer Res 1994) Proband 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 years plus another additional 1st or 2nd degree relative in the same lineage with any cancer <60 years

Li Fraumeni Syndrome 1969 Li and Fraumeni reviewed FH of 648 children with RMS and identified 5 families with another case of sarcoma 1982 Update follow-up of 4 families and description of an unusual familial clustering of cancers: - sarcomas - breast cancers - early-onset carcinomas - brain tumors 1990 Malkin et al. identify p53 germline mutations in 5 LFS families

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

Age distributions of the major tumour sites in TP53 mutation carriers Olivier et al., Cancer Res 2003 Age at onset 0-10 11-20 21-30 31-40 41-

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

IVS3 –11C>G (skipping of exon 4) 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

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) Mutations Tumours 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)

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

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

CASE MATERIAL 23 families with one case of sarcoma and one or more cases of breast carcinoma. Family classification LFS LFL non-LFS/non-LFL Total HBOC 2 5 13 20 non-HBOC 3 16 23 INT

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

RESULTS INT Germline mutations HBOC non-HBOC Total LFS LFL non-LFS/non-LFL TP53 1 2* 3* BRCA1 BRCA2 None identified 2 12 3 18 5* 13 23* *one case carried both a TP53 and BRCA2 mutations INT

* Family no. 7

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. 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 INT

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

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