Inherited Breast and Ovarian Cancer

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Inherited Breast and Ovarian Cancer and Modern
Women
HGM 2006 - Helsinki 1 June 2006
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Rose Frisch, 2003
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(No Transcript)
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BRCA1 and BRCA2
gt1000 mutations of BRCA1 gt1000 mutations of
BRCA2 All cancer-associated mutations are
individually rare
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Family 1. BRCA1.2800 DAA
2-hit model for adult onset cancers
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Family 16. BRCA2.1529 D AAAG 456 stop
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Family 77. BRCA1.5677insA 1853 stop
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Functions of BRCA1 Ubiquitination, DNA repair,
transcriptional regulation
RING
BRCT
1575 1863
1 110
p53
RAD51
BRCA2
BARD1
BAP1
MSH2
RB1
UBCH5C
CtIP
ZBRK1
ATF1
RNA Hel A
RAD50
E2F
HDAC 1/2
RNA Pol II
MSH2
p300/CBP
ERa
BACH1
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Family 4. BRCA1. 300 G gt C Cys 61 Gly
Point mutation in RING domain
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BRCA1
BARD1
4-helix bundle
Site I
Site I
Central helix
Site II
Peter Brzovic Rachel Klevit
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BRCA1
BARD1
Loss of ubiquitin ligase activity
4-helix bundle
Site I
Site I
Central helix
Site II
Peter Brzovic Rachel Klevit
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D 307 aa from BRCT domain
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Family 87. BRCA1. D 69226-80582 D exons 20-22
exon 20 71598-71681 exon 21 77620-77674 exon
22 79543-79616
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Duplications and deletions at BRCA1 and BRCA2 in
300 families
Blue BRCA1 and BRCA2 genes, red deletions,
yellow duplications
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Duplications and deletions at BRCA1 and BRCA2 in
300 families
Blue BRCA1 and BRCA2 genes, red deletions,
yellow duplications
12 of high-risk families with wildtype
commercial test results carry genomic
rearrangements at BRCA1 or BRCA2
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What are the risks of breast and ovarian cancer
due to inherited mutations in BRCA1 or
BRCA2? New York Breast Cancer Study
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Trace mutations through the families, then
determine cancer experience of female relatives
with mutations
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Risk of breast cancer for relatives with BRCA1 or
BRCA2 mutations not selected for age at diagnosis
or family history
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Families with BRCA1/2 mutations with low
incidence of cancer
Are these families low risk (as well as low
incidence)?
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Risk of breast cancer for relatives with BRCA1 or
BRCA2 mutations Low-incidence families
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Low cancer incidence in an extended family By
chance, distant female relatives do not carry
mutations
BRCA2 6174DT
Complete genotyping is important
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High cancer incidence among female relatives with
mutation
BRCA1 5382insC
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Risk of breast cancer for relatives with BRCA1 or
BRCA2 mutations Effect of birth cohort
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Age at breast cancer diagnosis among probands by
genotype and pregnancy history, adjusted for
birthyear
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Age at breast cancer diagnosis among probands
with BRCA mutations by physical activity as a
teenager, adjusted for birthyear
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Risk of ovarian cancer for relatives with BRCA1
or BRCA2 mutations
.02
.21
.40
.46
.54
BRCA1
BRCA2
.02
.02
.06
.12
.23
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Occult cancers detected at prophylactic surgery
291.BRCA1.3795 D4
294.BRCA1.2800DAA
295.BRCA1.2800DAA
Fallopian tube early invasive
Fallopian tube in situ
Primary peritoneal IIIc
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Mutations in CHEK2 associated with breast cancer
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Proportion of familial breast cancer due to
mutations in known genes
All families
Female breast cancer only
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Families with gt4 cases of breast cancer Wildtype
at BRCA1, BRCA2, CHEK2, p53, PTEN
300 more
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Haplotypes in the AJ population at the CHEK2
region of 22q
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Genome-wide screen for founder mutations in novel
genes Long haplotypes shared by multiple (not
all!) affected families
Mother-daughter pairs with breast cancer from a
founder population (AJ)
Sequence genes from longest haplotypes
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Phylogeny of haplotypes spanning 2MB on 8q
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Conclusions
Common disease - many, individually rare
alleles Second, somatic events due to genomic
structure Genetic heterogeneity of both loci and
alleles Reduced heterogeneity in founder
populations Haplotype length as a mapping
tool Indicator mutations where there is one,
there will be more..
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University of Washington Tom Walsh Silvia
Casadei Jake Higgins Kevin Roach Avraham
Shaag Sunday Stray Jessica Mandell Ming
Lee Elizabeth Swisher Peter Brzovic Rachel
Klevit
Share Zedek-Hebrew University Paul
Renbaum Ephrat Levy-Lahad
Czech and Slovak Republics Sona Ciernikova
Lenka Foretova Pavel Soucek
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Thank you for inviting me to Helsinki!