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
Milan, Italy
ISTITUTO FIRC
DI ONCOLOGIA
MOLECOLARE
Familial breast cancer cases
high-penetrance genes:
BRCA1 and BRCA2
20 %
5%
“less-penetrant”
genes: TP53, PTEN,
LKB1, ATM, CHEK2,
BRIP1, PALB2 and
other to be identified
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,
Olivier et al., Cancer Res 2003
teratoma, neuroblastoma
Age distributions of the
major tumour sites in
TP53 mutation carriers
Age at onset
0-10
11-20
21-30
31-40
41-
Olivier et al.,
Cancer Res 2003
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)
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
INT - Milano
IVS3 –11C>G (skipping of exon 4)
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
2000
Mutation negatives
1500
S
1000
S
500
0
Mutation detection rates
BRCA1/2
1
30%
TP53
2
13%
INT
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
0
0
3
3
Total
2
5
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
Germline
mutations
HBOC
LFS
LFL non-LFS/non-LFL
non-HBOC
Total
TP53
1
2*
0
0
3*
BRCA1
0
0
0
0
0
BRCA2
0
2*
1
0
3*
None identified
1
2
12
3
18
Total
2
5*
13
3
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 ?






