Arvelig brystkræft. Hvilke gener kender vi, og hvad er den ... - DBCG
Arvelig brystkræft. Hvilke gener kender vi, og hvad er den ... - DBCG
Arvelig brystkræft. Hvilke gener kender vi, og hvad er den ... - DBCG
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<strong>Arvelig</strong> <strong>brystkræft</strong><br />
h<strong>vi</strong>lke <strong>gen<strong>er</strong></strong> <strong>kend<strong>er</strong></strong> <strong>vi</strong> –<br />
<strong>og</strong> <strong>hvad</strong> <strong>er</strong> <strong>den</strong> kliniske betydning<br />
Anne-Marie G<strong>er</strong>des<br />
<strong>DBCG</strong>’s Genetiske udvalg
<strong>Arvelig</strong> mammacanc<strong>er</strong><br />
Tidlig debut<br />
Fl<strong>er</strong>e affic<strong>er</strong>ede familiemedlemm<strong>er</strong><br />
Bilat<strong>er</strong>al mammacanc<strong>er</strong><br />
Canc<strong>er</strong> i fl<strong>er</strong>e organ<strong>er</strong> især ovariecanc<strong>er</strong>
Genetisk udredning<br />
<strong>og</strong> rådgivning<br />
Kliniske kontroll<strong>er</strong><br />
profylaktisk op<strong>er</strong>ation<br />
Genetisk testning
Fordeling af mammacanc<strong>er</strong><br />
Sporadisk mammacanc<strong>er</strong><br />
70-80%<br />
Familiær mammacanc<strong>er</strong><br />
15-20%<br />
<strong>Arvelig</strong> mammacanc<strong>er</strong><br />
5-10%
Ex. sporadisk mammacanc<strong>er</strong><br />
livstidsrisiko
Familiær mammacanc<strong>er</strong><br />
(mod<strong>er</strong>atrisiko)<br />
15-20% af mammacanc<strong>er</strong> patient<strong>er</strong><br />
2 ell<strong>er</strong> fl<strong>er</strong>e tilfælde af mammacanc<strong>er</strong> i familien<br />
Ofte sen debut (>50 år)<br />
Ikke ovariecanc<strong>er</strong> i familien<br />
Raske ov<strong>er</strong>springende <strong>gen<strong>er</strong></strong>ation<strong>er</strong>
Ex. familiær mammacanc<strong>er</strong><br />
livstidsrisiko 20-29%<br />
I:1 I:2<br />
49<br />
II:1 II:2 II:3<br />
55<br />
45<br />
For indi<strong>vi</strong>dual: III:1<br />
Calculated risk of canc<strong>er</strong> (20<br />
Het<strong>er</strong>ozygote risk: 19.0%<br />
10 year risk: 0.9%<br />
20 year risk: 4.4%<br />
30 year risk: 9.7%<br />
Lifetime risk (85): 24.3%
<strong>Arvelig</strong> mammacanc<strong>er</strong><br />
(højrisiko)<br />
~5% af mammacanc<strong>er</strong> patient<strong>er</strong><br />
Mon<strong>og</strong>en dominant arvegang<br />
Kønsuafhængig arvegang<br />
Kønsafhængig penetrans<br />
Tidlig debut<br />
Forekomst af ovariecanc<strong>er</strong><br />
BRCA1,2-<strong>gen<strong>er</strong></strong>ne
Ex. arvelig mammacanc<strong>er</strong><br />
livstidsrisiko >30%<br />
II:1 II:2<br />
III:1<br />
30<br />
I:1 I:2<br />
52<br />
II:3<br />
53<br />
45<br />
For indi<strong>vi</strong>dual: III:1<br />
Calculated risk of canc<strong>er</strong> (30<br />
Het<strong>er</strong>ozygote risk: 35.6%<br />
Homozygote risk: 0.1%<br />
10 year risk: 6.1%<br />
20 year risk: 14.9%<br />
30 year risk: 22.8%<br />
Lifetime risk (85): 35.3%
<strong>Arvelig</strong> canc<strong>er</strong> - g<strong>er</strong>mline mutation Sporadisk canc<strong>er</strong> - somatisk mutation<br />
Tumorcelle<br />
Somatiske<br />
forældrecell<strong>er</strong><br />
Kønscell<strong>er</strong><br />
Somatiske cell<strong>er</strong> i<br />
afkom<br />
Tumorcelle
Syndrom<strong>er</strong> med øget risiko for mammacanc<strong>er</strong><br />
Mamma-ovariecanc<strong>er</strong> syndrom<br />
Cow<strong>den</strong>’s syndrom<br />
Li-Fraumeni’s syndrom<br />
Het<strong>er</strong>ozygoti for ataxia telangiectasi<br />
<strong>Arvelig</strong>t malignt melanom (dysplastisk nævus syndrom)<br />
Peutz-Jaegh<strong>er</strong>’s syndrom<br />
Klinefelt<strong>er</strong>’s syndrom<br />
Lobulær mammacanc<strong>er</strong> <strong>og</strong> linitis plastica
Genetisk udredning<br />
<strong>og</strong> rådgivning<br />
Kliniske kontroll<strong>er</strong><br />
profylaktisk op<strong>er</strong>ation<br />
Genetisk testning
Fordeling af mammacanc<strong>er</strong><br />
Sporadisk mammacanc<strong>er</strong><br />
70-80%<br />
Familiær mammacanc<strong>er</strong><br />
15-20%<br />
<strong>Arvelig</strong> mammacanc<strong>er</strong><br />
5-10%
Mammacanc<strong>er</strong> susceptibility <strong>gen<strong>er</strong></strong>*<br />
Lav-penetrans allel<strong>er</strong><br />
Ex: FGFR2, TNRC9, MAP3K1,<br />
LSP1, (8q), (2q), CASP8<br />
*Stratton MR et al. Nat Genet 2008<br />
Mod<strong>er</strong>at-penetrans <strong>gen<strong>er</strong></strong><br />
Ex: ATM, BRIP1, CHEK2, PALB2<br />
Høj-penetrans <strong>gen<strong>er</strong></strong><br />
Ex: BRCA1, BRCA2,<br />
TP53, PTEN
Mammacanc<strong>er</strong> susceptibility <strong>gen<strong>er</strong></strong><br />
????<br />
* G<strong>er</strong>des AM et al. Clin Genet 2006<br />
BRCA1, BRCA2*<br />
PTEN, TP53, ATM, CDKN2A, CHEK2,<br />
STK11, CDH1, BRIP1, PALB2
DNA repair<br />
DNA BRCA pathway repair<br />
BRCA1<br />
BRCA1<br />
BRCA2 RAD51 Failed DNA repair<br />
p53+<br />
p53<br />
BRCA2<br />
RAD51<br />
p53-<br />
p53<br />
Checkpoint activation<br />
p21<br />
p21<br />
Cell cycle arrest Unregulated growth
BRCA1:<br />
Livstidsrisici for canc<strong>er</strong> for<br />
BRCA1,2-mutationsbær<strong>er</strong>e<br />
Mammacanc<strong>er</strong>: 80%<br />
Ovariecanc<strong>er</strong>: 50%<br />
Salpinxcanc<strong>er</strong><br />
Bilat<strong>er</strong>al mammacanc<strong>er</strong><br />
BRCA2:<br />
Mammacanc<strong>er</strong>: 80%<br />
Ovariecanc<strong>er</strong>: 25%<br />
Bilat<strong>er</strong>al mammacanc<strong>er</strong><br />
Mandlig mammacanc<strong>er</strong><br />
Prostata, pancreas,<br />
thyreoidea, larynx,<br />
gastrointestinal canc<strong>er</strong>
Genetisk testing<br />
I<strong>den</strong>tifikation af familiens mutation<br />
H<strong>vi</strong>s mutationen i<strong>den</strong>tific<strong>er</strong>es:<br />
• prædiktiv genetisk testing af raske slægtninge:<br />
• -mutation: canc<strong>er</strong>risiko som befolkningen<br />
• +mutation: høj canc<strong>er</strong>risiko - follow up<br />
H<strong>vi</strong>s mutationen ikke i<strong>den</strong>tific<strong>er</strong>es:<br />
• stamtavlen basis for risikovurd<strong>er</strong>ing<br />
• follow up af alle nære slægtninge
Gentest for mammacanc<strong>er</strong><br />
susceptibility <strong>gen<strong>er</strong></strong> i klinikken<br />
Forudsætning<strong>er</strong><br />
Kendskab til canc<strong>er</strong>risiko hos anlægsbær<strong>er</strong>e<br />
Sikk<strong>er</strong>hed for at canc<strong>er</strong>risiko ikke <strong>er</strong> forhøjet<br />
hos ikke-anlægsbær<strong>er</strong>e<br />
Tilbud om e<strong>vi</strong><strong>den</strong>sbas<strong>er</strong>et klinisk follow up
318 BRCA1/2 famili<strong>er</strong> i DK<br />
(April 2006)*<br />
203 BRCA1 (63.8%)<br />
115 BRCA2 (36.2%)<br />
Analyse for kendt mutation (395):<br />
269 BRCA1: 199 ♀ 68 ♂<br />
126 BRCA2: 103 ♀ 23 ♂<br />
*Thomassen M et al. Acta Oncol 2008
713 BRCA anlægsbær<strong>er</strong>e<br />
400<br />
350<br />
300<br />
250<br />
200<br />
150<br />
100<br />
50<br />
0<br />
391<br />
BRCA1<br />
female<br />
79<br />
BRCA1<br />
male<br />
210<br />
BRCA2<br />
female<br />
31<br />
BRCA2<br />
male
120<br />
100<br />
80<br />
60<br />
40<br />
20<br />
BRCA1/2 famili<strong>er</strong> på<strong>vi</strong>st i Vest-DK vs. Øst-DK<br />
0<br />
102<br />
(50%)<br />
101<br />
(50%)<br />
66<br />
(57%)<br />
BRCA1 BRCA2<br />
49<br />
(43%)<br />
VestDK<br />
ØstDK
Found<strong>er</strong> BRCA1/2 mutation<strong>er</strong> i DK?<br />
BRCA1<br />
185delAG (3%)<br />
234T>G (2%)<br />
249T>A (2%)<br />
300T>G/C>T (4%)<br />
1806C>T (3%)<br />
2594delC (16%)<br />
2595delA (2%)<br />
3172ins5 (3%)<br />
3438G>T (9%)<br />
3726C>T (3%)<br />
3829delT (5%)<br />
5332G>A (3%)<br />
5382insC (8%)<br />
del exon 3-16 (3%)<br />
BRCA2<br />
373G>T (3%)<br />
1538del4 (10%)<br />
3036del4 (3%)<br />
3058A>T (3%)<br />
4075delGT (5%)<br />
5982delTA (3%)<br />
6601delA (11%)<br />
6714del4 (9%)<br />
7297delCT (3%)<br />
8702delC (3%)<br />
9243delAT (3%)<br />
IVS13-1G>A (3%)
BRCA1/2 mutation<strong>er</strong> i DK<br />
Lighed<strong>er</strong>:<br />
Sv<strong>er</strong>ige (Sydlige)<br />
Norge<br />
Polen<br />
Baltiske lande<br />
Rusland<br />
Vest Europa<br />
Australien<br />
Forskelle:<br />
Norge<br />
Finland<br />
Island<br />
Frankrig<br />
Spanien<br />
Holland<br />
Asien
Norge<br />
Sv<strong>er</strong>ige<br />
VestEuropa<br />
Baltiske lande<br />
Sv<strong>er</strong>ige<br />
Danske BRCA<br />
mutation<strong>er</strong> origin<br />
VestEuropa m.fl.
Genetisk udredning<br />
<strong>og</strong> rådgivning<br />
Kliniske kontroll<strong>er</strong><br />
forebyggende op<strong>er</strong>ation<br />
Genetisk testning
Klinisk und<strong>er</strong>søgelsespr<strong>og</strong>ram<br />
Behandling af syge familiemedlemm<strong>er</strong><br />
Regelmæssige kontroll<strong>er</strong> af raske familiemedlemm<strong>er</strong><br />
(Prænatal diagnostik)
Klinisk follow up<br />
Mammae Ovari<strong>er</strong><br />
BRCA1/2 positive:<br />
• årlig mamm<strong>og</strong>rafi 30-70 år<br />
• screeningsmamm<strong>og</strong>rafi 70+ år<br />
• MR scan 25-70 år<br />
• evt. profylaktisk mastektomi<br />
Højrisiko:<br />
• årlig mamm<strong>og</strong>rafi 30-50 år<br />
• screeningsmamm<strong>og</strong>rafi 50-70 år<br />
Mod<strong>er</strong>atrisiko:<br />
• årlig mamm<strong>og</strong>rafi 40-50 år<br />
• screeningsmamm<strong>og</strong>rafi 50-70 år<br />
Højrisiko:<br />
Årligt fra 30 år:<br />
•vaginal UL<br />
•CA125<br />
Eft<strong>er</strong> endt reproduktion:<br />
•profylaktisk BSO<br />
(bilat<strong>er</strong>al salpingoooforektomi)<br />
www.dbcg.dk
Profylaktisk BSO ved BRCA-positive<br />
• Restrisiko for p<strong>er</strong>itoneal carcinomatose
Tak til alle samarbejdspartn<strong>er</strong>e<br />
patient<strong>er</strong>ne <strong>og</strong> d<strong>er</strong>es famili<strong>er</strong>
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