P53 E TUMORE MAMMARIOP53 E TUMORE MAMMARIO

Paolo RadicePaolo Radice

ISTITUTO NAZIONALE ISTITUTO NAZIONALE PER LO STUDIO E LAPER LO STUDIO E LACURA DEI TUMORICURA DEI TUMORI

ISTITUTO FIRC ISTITUTO FIRC DI ONCOLOGIA DI ONCOLOGIA MOLECOLAREMOLECOLARE

Milan, Italy

Prospettive sul tumore della Prospettive sul tumore della mammella:mammella:

nuove osservazioni, quali opportunità?nuove osservazioni, quali opportunità?Cremona, 24 maggio 2008Cremona, 24 maggio 2008

Familial breast cancer casesFamilial 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 %

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

the p53 protein

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

Li Fraumeni SyndromeLi Fraumeni Syndrome

19691969 Li and Fraumeni reviewed FH of 648 children with Li and Fraumeni reviewed FH of 648 children with

RMS and identifiedRMS and identified

5 families with another case of sarcoma5 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 LFLDiagnostic criteria for LFS and LFL

Li-Fraumeni syndrome Li-Fraumeni syndrome (Li et al., Cancer Res 1988)(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 plus additional 1st or 2nd degree relative in the same lineage aged <45

years with any cancer or a sarcoma at any ageyears with any cancer or a sarcoma at any age

Li-Fraumeni syndrome Li-Fraumeni syndrome (Birch et al., Cancer Res 1994)(Birch et al., Cancer Res 1994)

• Proband with any childhood tumour, or sarcoma, brain tumour, or adrenocortical tumour <45 Proband with any childhood tumour, or sarcoma, brain tumour, or adrenocortical tumour <45

yearsyears

• plus additional 1st or 2nd degree relative in the same lineage with typical LFS tumour at any plus additional 1st or 2nd degree relative in the same lineage with typical LFS tumour at any

age or any cancer <45 years age or any cancer <45 years

• plus another additional 1st or 2nd degree relative in the same lineage with any cancer <60 plus another additional 1st or 2nd degree relative in the same lineage with any cancer <60

yearsyears

Li Fraumeni SyndromeLi Fraumeni Syndrome

19691969 Li and Fraumeni reviewed FH of 648 children Li and Fraumeni reviewed FH of 648 children with with RMS and identifiedRMS and identified

5 families with another case of sarcoma5 families with another case of sarcoma

19821982 Update follow-up of 4 families and description of

an unusual familial clustering of cancers:

- sarcomas

- breast cancers

- early-onset carcinomas

- brain tumors19901990 Malkin et al. identify p53 germline mutations in

5 LFS families

Tumour specrtum in families TP53 germline Tumour specrtum in families TP53 germline mutations mutations

*

*prostate, pancreatic, bladder, hepatocellular, naso-pharyngeal and laryngeal ca, Wilms tumour, hepatoblastoma, melanoma, teratoma, neuroblastoma Olivier et al., Cancer Res 2003

0-10 11-20 21-30 31-40 41-

Age at onset

Age distributions of the Age distributions of the major tumour sites in major tumour sites in TP53 mutation carriersTP53 mutation carriers

Olivier et al., Cancer Res 2003

Multiple primary tumours in LFSMultiple primary tumours in LFS

15 %15 % developed a 2developed a 2ndnd cancer cancer (interval 1-27 years)(interval 1-27 years)

relative risk is higher if 1relative risk is higher if 1stst tumor diagnosed in infancy tumor diagnosed in infancy

4 %4 % developed a 3developed a 3rdrd cancer cancer

2 %2 % developed a 4developed a 4thth cancer cancer

among patient who developed a 2among patient who developed a 2nd nd tumor a consistent fraction tumor a consistent fraction

had receivedhad received previous radiotherapyprevious radiotherapy (interval 3-22 years, tumors in RT field)(interval 3-22 years, tumors in RT field)

A LFS family pedigree

leiomiosarcoma 15 aacarcinoma mammella dx 25 aacarcinoma mammella sx 27 aacarcinoma corteccia surrenale 27 aa

TP53 gene mutation

IVS3 –11C>G (skipping of exon 4)INT - Milano

Genotype-phenotype correlations in LFSGenotype-phenotype correlations in LFS

TP53 mutations are detectable in 50-70% of LFS families, but TP53 mutations are detectable in 50-70% of LFS families, but only in 20% of LFL familiesonly in 20% of LFL families ( (Varley et al., Br J Cancer 1997)Varley et al., Br J Cancer 1997)

MutationsMutations TumoursTumours

Missense mutatios in the Missense mutatios in the DNA binding domainsDNA binding domains

Brain tumoursBrain tumours

Missense mutations outside Missense mutations outside DNA binding domainsDNA binding domains

Adrenal tumoursAdrenal tumours

‘‘Null’ mutationsNull’ mutations Brain tumours (early onset)Brain tumours (early onset)

(Olivier et al., Cancer Res 2003)

Mutation screenings in Mutation screenings in Hereditary Breast Cancer*Hereditary Breast Cancer*

BRCA1/2 TP53Mutation detection rates 30% 13%

*as of April 2008

INT

Mutation positives

Mutation negatives

Germline mutations of TP53 and Germline mutations of TP53 and BRCA2 genes in breast BRCA2 genes in breast

cancer/sarcoma familiescancer/sarcoma families(Manoukian et al. Eur J cancer, 2007)(Manoukian et al. Eur J cancer, 2007)

INT

AIMAIM

To verify the involvement of To verify the involvement of BRCA1BRCA1 and and BRCA2BRCA2 genes in breast cancer/sarcoma families genes in breast cancer/sarcoma families unlinked to unlinked to TP53.TP53.

CASE MATERIALCASE MATERIAL

• 23 families with one case of sarcoma 23 families with one case of sarcoma and one or more cases of breast and one or more cases of breast carcinoma.carcinoma.

INT

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

Diagnostic criteria for HBOCDiagnostic criteria for HBOC

• Three or more first degree relatives* affected with Three or more first degree relatives* affected with breast cancer or ovarian cancer at any agebreast 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 breast cancer < 50 years plus breast cancer bilateral at

any ageany age• breast cancer < 50 years plus ovarian cancer at any breast cancer < 50 years plus ovarian cancer at any

ageage• breast cancer < 50 yrs plus male breast cancer at any breast cancer < 50 yrs plus male breast cancer at any

ageage• ovarian cancer at any ageovarian cancer at any age *or second degree relatives if in paternal lineage

INT

RESULTSRESULTS

INT

Germline mutations

HBOCnon-HBOC

TotalLFS LFL non-LFS/non-LFL

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

*

Family no. 7Family no. 7

CONCLUSIONS• The screening of The screening of BRCA2BRCA2, in addition to , in addition to TP53TP53, may be , may be appropriate for the molecular characterisation of appropriate for the molecular characterisation of breast cancer/sarcoma families, with practical breast cancer/sarcoma families, with practical implications for counselling and clinical management.implications for counselling and clinical management.

INT

• Although we could not provide evidence that Although we could not provide evidence that BRCA2 BRCA2 mutations are associated with an increased risk of mutations are associated with an increased risk of sarcoma, our results indicate that the presence of sarcoma, our results indicate that the presence of these malignancies in HBOC families is not a these malignancies in HBOC families is not a negative predictor of mutations of negative predictor of mutations of BRCA2BRCA2..• The role of The role of BRCA1BRCA1 in breast/sarcoma families in breast/sarcoma families remains undeterminedremains undetermined

FONDAZIONE IRCCS ISTITUTO NAZIONALE TUMORI (INT), MILANOSiranoush ManoukianBernard PeisselSilvia StacchiottiMonica TerenzianiGraziella PasquiniSimona FrigerioMarco A. PierottiGabriella Della Torre

FONDAZIONE ISTiTUTO FIRC DI ONCOOGIA mOLECOLARE (IFOM),

MILANOValeria PensottiFloriana BarberaISTITUTO EUROPEO DI ONOCLOGIAMonica Barile

UNIVERSITA’ DI MODENA E REGGIO EMILIALaura Cortesi

Follow-up in LFSFollow-up in LFS

avoid RX, MX, TC ??avoid RX, MX, TC ?? avoid environmental carcinogensavoid environmental carcinogens healthy life stilehealthy life stile

be alert for early signs of cancerbe alert for early signs of cancer

annual clinical examinationannual clinical examination abdomen ultrasound < age 16abdomen ultrasound < age 16 breast clinical examination every 6 months + MRI / breast US breast clinical examination every 6 months + MRI / breast US

> 25 yrs> 25 yrs annual brain MRIannual brain MRI gastroscopy, Hemoccultgastroscopy, Hemoccult blood cell counts ?blood cell counts ?