Post on 23-Jan-2016
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유방암의 Genetic Screening
영남의대 병리학교실배 영 경
Breast cancer
Breast cancer susceptibility genes
Syndrome Gene Inheritance (%)*
Cancers
Breast/ovarian cancer syndrome
BRCA1 AD (60-80) Breast, ovary, colon
BRCA2 AD (60-85) Breast, ovary, prostate, pancreas
Li-Fraumeni syndrome TP53 AD (100) Breast, brain, sarcoma, leukemia, adrenocortical carcinoma
Cowden disease PTEN AD (20-30) Breast, ovary, thyroid, colon
Peutz-Jegher syndrome
STK11/LKB1 AD
(RR: 20.3 folds)
GIT, breast
Ataxia-telangiectasia ATM AD Breast
Site-specific CHEK2 AD Breast
Muir-Torre/HNPCC MSH2/MLH1 AD Colorectal, breast
*Breast cancer penetrance in mutation carriers
Problems in genetic screening of breast cancer
• No unifying molecular alteration in sporadic breast cancer (genetically heterogeneous)
• Low incidence of BRCA1/BRCA2 mutation in breast cancer
• Large size of BRCA1/BRCA2 genes• No specific loci of mutation on BRCA1/BRCA2 genes • High cost: not covered by insurance• No domestic data of penetrance/cancer risk for BRCA1
/BRCA2 mutation carriers
Germline mutation of BRCA1 & BRCA2
15-20% of familial breast cancer
5% of breast cancer overall
BRCA1
• Lifetime breast cancer risk: 60-80%
• Lifetime ovarian cacner risk: 20-40%
• Increased risk for prostate and colon cancer
• Cell cycling, DNA-damage response
BRCA2• Lifetime breast cancer
risk: 60-85%• Lifetime ovarian cancer
risk: 10-20%• Lifetime male breast
cancer risk: 6%• Increased risk for colon,
prostate, pancreas, GB, bile duct, stomach cancer and malignant melanoma
• Maintenance of chromosome integrity
Cancer risk in women with germline BRCA1 mutations
Nature Med 7: 552-6, 2001
Incidence of BRCA1/BRCA2 mutation
• Non-cancer populationAshkenazi Jews: BRCA1: 1%, BRCA2: 1%
General population: BRCA1: 0.06%
• Breast cancer patientsUnselected groups: BRCA1: 1.4%, BRCA2: 1.2%
Early onset breast cancer patients (<45 yrs)
BRCA1: 6-13% , BRCA2: 4-5%
• Families with both breast and ovarian cancer BRCA1 &BRCA2: 55%
• Families with both breast and ovarian cancer in the same individual
BRCA1 &BRCA2: 75%
Incidence of BRCA1/BRCA2 mutation in Korean Breast Cancer
BRCA1 (%) BRCA2 (%) Total (%)
Unselected
Kim et al. 1.4 1.2
Ahn et al. 1.8 1.0 2.8
Selected
Ahn et al.* 8.7 4.0 12.7
Choi et al.# 10 8.7 15
*: High-risk patients with family history of breast or first-degree ovarian cancer, bilateral breast cancer, male breast cancer, multiple organ cancer, earlier age of onset(<35 yr).
#: Early onset breast cancer patients: <40 yr
• ER-negative• PR-negative• Cyclin D1-negative• HER-2/neu-negative• P53-positive• High nuclear and histologic grade
BRCA mutation carriers’ tumors
F-CSGE or DHPLC Direct sequencing
Analysis of BRCA1/BRCA2 mutation
BRCA1-exon24‘ATTGGGCA’ deletion
Limitation of widespread BRCA1/BRCA2 testing
• Expensive cost
• Uncertain clinical value of a positive test result
• Fear of loss of health
Cost of genetic screening
• 한국요양급여비용의 100 분의 100 을 본인이 부담하는 항목돌연변이검사 ( 확진 )
121 다 .
유전성유방암 / 난소암 BRCA1, BRCA2 305,740원
• 미국$ 2400 – 2975 for both BRCA1 and BRCA2
• Expensive screening test
• Uncertain clinical value of a positive test result
• Fear of loss of health
Limitation of widespread BRCA1/BRCA2 testing
Results of mutation analysis
1) Over 800 different mutations are found throughout the entire gene sequence
2) Nonsense or frame shift mutations
protein truncation
Missense mutation
undetermined clinical significance
3) No founder mutations in Korean
e.g.) Ashkenazi Jew, Iceland
4) No domestic data for penetrance of BRCA mutation
Cumulative risk of breast cancer by age in women from families with cancer-predisposing mutations
Age
Age Cumulative Risk
BRCA1 BRCA2
30 yrs 3.2% 4.6%
40 yrs 19.1% 12%
50 yrs 50.8% 46%
60 yrs 54.2% 61%
70 yrs 85% 86%
Easton et al., 1995 and 1997
Limitation of widespread BRCA1/BRCA2 testing
• Expensive cost
• Uncertain clinical value of a positive test result
• Fear of loss of health
Advantages to testing for BRCA mutations
• Women may feel relieved knowing for certain whether or not they are at a higher risk for breast cancer.
• Women with breast cancer may have better responses to certain treatments that are specifically designed for BRCA positive patients.
• Women may take preventive measures to help reduce their risk of breast cancer if they are positive for BRCA mutations.
• Other family members may decide if they wish to be tested for BRCA mutations based on the results of a woman’s test.
Disadvantages to testing for BRCA mutations
• Women may become worried, panicked, or stressed if they discover they have a higher than average risk for breast cancer.
• Women who test positive for BRCA mutations are faced with the difficulty of telling family members
• Women who test negative for BRCA mutations may falsely believe they will never get breast cancer.
Genetic Screening
• Who to screen
• Who may not need screen
• How reducing the incidence and morbidity of breast cancer
• How reducing health care cost
• How benefiting women, their families, and society
Models for prediction of BRCA1/BRCA2 mutations (by NCI)
• Personal characteristics• Breast cancer diagnosed at an early age• Bilateral breast cancer• A history of both breast and ovarian cancer• The presence of breast cancer in 1 or more male family
members
• Family characteristics• Multiple cases of breast cancer in the family• Both breast and ovarian cancer in the family• One or more family members with 2 primary cancers• Ashkenazi Jewish background
Recommendation for BRCA mutation analysis
High-risk patients with
1) family history of breast or first-degree ovarian cancer
2) bilateral breast cancer
3) male breast cancer
4) multiple organ cancer including breast cancer
5) earlier age of onset (<35 yr)
Ahn et al. J Korean Med Sci 19: 269-74, 2004
Risk assessment of patients with a family history of breast cancer
Warner E, et al. Canadian Family Physician 45: 105-112, 1999.
One FDR > 50yr, orMore distant relative
One FDR < 50yr, two FDRs or male relative
Patient requests gene testing
Inherited risk education orGenetic counseling
No genetic risk or patient does not want gene testing
Patient desires further gene testing
Test for mutations in affected relatives
positive
Test for mutations in patient
positive
Routine breast cancer surveillance
negative
negative
Begin early surveillance programAge 18: monthly breast self-examinationsAge 25: monthly breast self-examinations annual clinical examinations annual mammograms Prophylactic mastectomy after childbearing?For those with BRCA1 mutation, annual CA-125 and pelvic ultrasound examinations prophylactic oophorectomy after age 40?
positive
Suggested algorithm for genetic screening based on recommendations by the National Institutes of Health and the National Human Genome Research Institute.
The Johns Hopkins Breast and Ovarian Surveillance Service (BOSS)
• review family history and other risk factors • provide individualized risk assessment • perform a clinical breast exam and instruct patients in
breast self-exam • discuss and offer genetic testing to evaluate inherited
cancer susceptibility • provide individualized cancer prevention and
screening information • discuss the benefits and risks of hormone
replacement therapy • provide information about chemoprevention of breast
cancer in high risk women
What to do?
• Select high-risk family• Genetic counselor• Give information for genetic testing• Explore the clinical significance of unverified
mutations • Develop standardized protocol for genetic
testing and follow-up of mutation carriers• Support the cost of genetic testing for the
high-risk family