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29 10 20 26
1
2013 5
2015 3
2
3
1.
2.
3.
4. HBOC
5.
4
AT
CG
C
G
AT
CG
5 6
7
1.
2.
3.
4. HBOC
5.
8
1. Genetic disorders
2.
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A)
B)22 46
C)
D)
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• Hereditary
• Sporadic
11
• (Germline mutation
(hereditary
• Somatic mutation
occur during tumor formation
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13 14
2015
•“ ”1 2 50%
• BRCA160-80%
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A
1
1
A
A 1
Knudoson 2
17
1.
2.
3.
4. HBOC
5.
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• 5
•
1
19 © 2009 NHS National Genetics Education and Development Centre Genetics and Genomics for Healthcarewww.geneticseducation.nhs.uk
Fig. 13.3 ©Scion Publishing Ltd
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0102030405060708090
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0102030405060708090
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1.
2.
3.
23 24
•
•
•
•
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2 1
2 13 1
63 2 1 47 2 1
2012
63%
55%
47%
26
(%)100
80604020
0
2 1
63 2 1 47 2 1
2012
10 20 30 40 50 60 70 80
(%)100
80604020
0
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1. 6 3
2.
3.
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29
1.
2.
3.
4. HBOC
5.
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Hereditary Breast and Ovarian Cancer : HBOC
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•2013 5 17
• ; 200815-19
•Cannon-Albright L A et al. Important Advances in Oncology. J. B. Lippencott Publishers, Philadelphia, 39-55, 1991
8 %1/12
14 28 % 40 70%
• 5 10
•
•2 4
•
32
• 15%
• 1/3 5%
15-20%
8 /
5
Newman B, et al. 1988, )
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10
p53
PTEN
MLH1, MSH2
APC, MYH
LKB1/STK11
ATM
BRCA X
40 50%
BRCA1 BRCA2
Hereditary Breast and Ovarian Cancer : HBOC
BRCA1 25-30% BRCA2 25-30% 50-60%
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Myriad myRisk™25
BR = BreastOV = OvarianCO = ColorectalEN = EndometrialME = MelanomaPA = PancreaticGA = GastricPR = ProstateOC = Other Cancers / Clinical Features
MYRIAD myRiskTM Clinical Handbook 35
HBOC
•• 20
•
•••••• BRCA1, BRCA2
:HBOC
Clavis Arcus36
BRCA1, BRCA2
DNADNA
BRCA1BRCA2 DNA
DNA 2
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RESEARCH ARTICLESA Strong Candidate for the Breast and Ovarian Cancer SusceptibilityGene BRCA1Yoshio Miki, Jeff Swensen, Donna Shattuck Eidens, et al.
Science. 1994 Oct 7;266(5182):66 71.
AbstractA strong candidate for the 17q linked BRCA1 gene, which influences susceptibility to breastand ovarian cancer, has been identified by positional cloning methods. Probable predisposingmutations have been detected in five of eight kindreds presumed to segregate BRCA1susceptibility alleles. The mutations include an 11 base pair deletion, a 1 base pair insertion,a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 geneis expressed in numerous tissues, including breast and ovary, and encodes a predicted proteinof 1863 amino acids. This protein contains a zinc finger domain in its amino terminal region,but is otherwise unrelated to previously described proteins. Identification of BRCA1 shouldfacilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals aswell as a better understanding of breast cancer biology.
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d.56y d.61y
BRCA1+
BRCA1(+)
BRCA1 ?
39
BRCA1/2
40
(variant of uncertainsignificance : VUS)
VUS41
BRCA1/2
BRCA1/2• BRCA1/2
•
BRCA1/2••
• HBOC•
HBOC)
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BRCA1/2
BRCA1/2
•
•
•
( )
43
HBOC
44
• 40%-85%
•40%-60%
• 15%-40%
1.2% 6.8
HBOC
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[ ]A: Meijers-Heijboer H et al. The New England Journal of Medicine 345(3):159-164, 2001B: Rebbeck TR et al. Journal of Clinical Oncology 22(6):1055-1062, 2004
(case) (control)
76 0 63 8 - A
1052
(1.9%)378
184(48.7%)
90% B
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[ ] Finch A et al. JAMA 296(2):185-192, 2006
BRCA1/2-
80% reduction
* */100,000/ )
1,262 32 1,0151,034 7 217
*
80%; 0.20 95 ; 0.07-0.58 P = 0.003
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1.
2.(NCCN )
3.
4.
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1.
2.
3.
4. HBOC
5.
49 50
1. BRCA
BRCAPARP
BRCA
2.DNA
PD1 PD-L1
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BRCA1/2
DNA
PARP
PARP BRCA1/2 synthetic lethal therapy
BRCA1/2PARP
DNA
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PD 1 Blockade in Tumors with Mismatch Repair DeficiencyDung T. Le, et al. N Engl J Med Volume 372(26):2509 2520 June 25, 2015
DNA
DNA
DNA
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HBOC http://hboc.jp/index.html
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•
••
•
55
• (G FISH )
• NIPT
•• Lynch
( )
••
•• QT
••
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