1. 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

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

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
1982 Update 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)
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

7. 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

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

11. 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

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)
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)

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

14. 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

15. 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

16. 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

17. 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

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.
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

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 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 ?