Transcript Breast Cancer Genetics in the Jewish Population

Breast Cancer Genetics
and the
Sephardic Jewish Woman
Sephardic Community Center
March 26, 2008
Heredity Predisposition to Breast and
Ovarian Cancer Among Sephardic Jewish
Women
Ruth Oratz, M.D.
Harry Ostrer, M.D.
NYU School of Medicine
Breast and Ovarian
Cancer Statistics - 2008
In 2008, 243.000 Americans will be diagnosed with breast or
ovarian cancer and 56,000 will die from their disease (Cancer
is the second leading cause of death in U.S.)
>150 deaths per day
5-10% of people with cancer have a significant
family history, suggesting a genetic predisposition
Jemal, et al, Cancer 2008. CA Cancer J Clin
How is breast cancer diagnosed?
 Palpable mass in the breast
 Self examination
 Physician examination
 Breast Imaging
 Mammogram
 Sonogram (Ultrasound)
 MRI
 Biopsy
 FNA
 Core biopsy
 Mammotome biopsy
 Excisional biopsy
Clinical Presentation of Breast Cancer Biology
 Breast cancer is not one
disease
 Spectrum of clinical
presentations
 Biology of breast cancer
 Histology
 Ductal
 Lobular
 In situ/Invasive
 Molecular Features
 ER/PR
 Her 2 neu
 Proliferation Index
Clinical Presentation of Breast Cancer Stage




TNM Classification
Tumor size
Lymph node involvement
Spread beyond local area
 Treatment based on stage and






biology
Surgery
Radiation therapy
Systemic therapy
Hormonal therapy
Chemotherapy
Biologic therapy
What are risk factors ?
 Anything that affects your
chance of getting a disease,
such as cancer.
 Smokinglung cancer
 Sun exposure skin cancer
 Relationship between having
risk factors and getting
disease
 Different kinds of risk factors.:
 Age, gender – can’t be changed
 Environmental
 Behavioral - diet, exercise
 Some factors influence risk
more than others,
 Risk for breast cancer can
change over time
Risk Factors for Breast Cancer
 Personal history of breast cancer
 Age
 Time of menarche
 Time of menopause
 Age of first term pregnancy
 Hormone Replacement Therapy/Oral Contraceptives
 Abnormal breast biopsy
 Previous chest irradiation
 Obesity/Physical Activity
 Alcohol
Family history as a Risk Factor for
Breast Cancer
Family History and Breast Cancer
 Breast cancer risk is higher
among women whose close
blood relatives have this
disease
 20%-30% of women with
breast cancer have a family
history
 One first degree relative
(mother, sister, daughter)
 Doubles risk
 Two first degree relatives
 5 fold increase
 Male with breast cancer
Genetic mutations contribute to
cancer development
Genetic Basis of Cancer
5-6 Hits in the Tumor Cell DNA
Heritable mutations
Chromosomal loss or
rearrangement
Risk Factors
Radiation
Smoking
Dietary carcinogens
Somatic mutations
What is the Evidence for a Hereditary
Predisposition to Cancer?
Twin Studies
Concordance rates %
MZ
DZ
>
Hereditary

Environmental
Monozygotic Dizygotic
twins
twins
Breast
14
9
Colorectum (men)
9
8
Colorectum (women)
16
6
Ovary
5
1
Prostate
21
6
Lichtenstein P. N Engl J Med. 343:78-85, 2000
More than one affected individual in the same
family, frequently in succeeding generations
Early age of onset
Multiple primary tumors
Non-random associations (i.e. breast and
ovary)
Male breast cancer
Percentage of Cancer that is Hereditary
Type of
Cancer
% Hereditary
Cases per year
# Hereditary
Breast
female
male
5-10%
11-22,000
15%
217,450
216,000
1,450
Ovarian
5-10%
26,000
1,300-2,600
Colorectal
5-10%
147,000
7-15,000
Prostate
5-10%
230,000
11-23,000
Total
5-10%
654,450
30,300-62,600
Jemal, et al, Cancer 2004. CA Cancer J Clin 2004; 54:8-29
Breast Cancer Risk Estimates Based on Family
History
Affected relative
Age of affected
relative
Cumulative risk (%)
by age 80
One first degree
<50
13-21
>50
9-11
<50
10-14
>50
8-9
Both < 50
35-48
Both >50
11-24
Both < 50
21-26
Both > 50
6-16
Two second degree
Two first degree
Two second degree
Hoskins, et al. JAMA273:577, 1995, adapted from Claus et al. Cancer 73:643, 1994
Inherited Susceptibility to
Breast Cancer
 5% - 10% of breast cancer
may be caused by inherited
susceptibility
 Genes related to increased
risk of breast cancer
 BRCA 1
 BRCA 2
 ATM
 CHEK 2
 P53 (Li-Fraumeni Syndrome)
 PTEN (Cowden Syndrome)
Genes Conferring High Risk for Breast and
Ovarian Cancer
Locus
Risk range
Associated syndrome
BRCA1
56-87% (by age 70)
Familial breast/ovarian cancer
BRCA2
37-84% (by age 70)
Familial breast/ovarian cancer
p53
50-89% (by age 50)
PTEN
30-40% (by age 50)
Brain, uterine, sarcomas, ovary,
breast
Thyroid, breast, uterine
MSH2, MLH1
70% (lifetime)
Colon, uterine, ovary, gastric,
bile duct
STK11
high
Breast, jejunum
BRCA GENES
 BRCA 1 - chromosome 17
 BRCA 2 – chromosome 13
 Mutations in these genes are
the most common ones
associated with breast &
ovarian cancer
 Tumor suppressor genes –
normally help to prevent
cancers from developing
 Mutations (abnormalities) in
the gene lead to dysfunction –
allowing or promoting cancer
development
Presumed Effects of Heritable
BRCA1 and BRCA2 Mutations
DNA damage
BRCA1 or BRCA2
mutation
Normal BRCA1 or BRCA2
failed DNA repair
DNA repair
Normal p53
cell death
p53 mutation
cancer
Does everyone with a BRCA
mutation develop cancer?
 Some individuals with BRCA mutations never
develop cancer
 This can make the cancer appear to skip generations
 Persons with a mutation, regardless of whether they
develop cancer, have a 50/50 chance to pass the
mutation on to the next generation.
BRCA GENES – Patterns of
Inheritance
Family Tree
Pedigree
Family with Multiple Cases of Breast
and Ovarian Cancer
Ov CA
Br CA 63
Ov CA 50
Ov CA36
Hereditary Breast Ovarian Cancer
Syndrome (BRCA1 / BRCA2)
 Early age onset breast cancer




(often before age 50)
Family history of both breast
and ovarian cancer
Family history of male breast
cancer
Increased chance of bilateral
cancers or an individual with
both breast and ovarian cancer
Increased incidence of tumors of
other specific organs
BRCA mutations
 BRCA 1 mutations
 36 percent to 85 percent lifetime
risk for breast cancer (in
females)
 40 percent to 60 percent lifetime
risk for second breast cancer
(not reappearance of first
tumor)
 20 percent to 60 percent lifetime
risk for ovarian cancer
 increased risk for other cancer
types, such as prostate cancer
 BRCA 2 mutations
 36 percent to 85 percent lifetime
risk for breast cancer (in
females)
 6 percent lifetime risk for breast
cancer (in males)
 up to 27 percent lifetime risk for
ovarian cancer
 increased risk for other cancer
types, such as pancreatic,
prostate, laryngeal, stomach
cancer, and melanoma
Genetic Counseling?
 Genetic counseling
 Trained professional

– genetic counselor, physician
Make the right diagnosis

Determine which, if any, test is appropriate

Provide a precise estimate of risk

Provide accurate information about results, prevention,
surveillance, treatment

Extend testing to family members

Genetic Counseling for Cancer Risk:
Who Should Be Tested?
1. Test the proband first.
2. If positive, offer testing to other family members
3. Do not recommend screening or random testing
Who should consider genetic testing for BRCA
mutations ?
 Affected individuals
 Early age breast cancer
 Family history
breast/ovarian cancer
 Breast & Ovarian cancer
in same individual
 Unaffected individuals
 No personal cancer
history
 Known mutation carrier
in family
 High risk family history
What is Genetic Testing?
 Blood sample is taken
 Genes (DNA) in blood is
analyzed
 Specific mutation
 Multisite 3 mutations
 3 most common mutations
found in Ashkenazi Jewish
populations
 Gene sequencing
How Do We Use the Information: Increased Surveillance
Breast cancer
Self-exam
Mammography
Ultrasound/MRI
Colon cancer
Colonoscopy
Ovarian cancer Ultrasound
CA125
Prostate cancer
Digital exam
PSA
Ultrasound
Breast Cancer Surveillance
 Screening
 Diagnosis
 Monitor for recurrence
 Watch for contralateral breast
cancer
 Techniques
 Self Exam
 Physician Exam
 Mammogram
 Ultrasound
 MRI
How Do We Use the Information: Risk-Reducing Surgery
or Chemoprevention?
Breast cancer
Hormonal manipulation
Prophylactic mastectomy
Colon cancer
Diet
Aspirin/NSAID
Total colectomy
Ovarian cancer Hormonal manipulation
Prophylactic oophrectomy
Prostate cancer Hormonal manipulation
Diet
Ovarian Cancer: Screening and Prevention
 Detection
 History & Physical





Exam
Family History
Transvaginal Pelvic
Sonogram
? CA 125
? New serum markers
Clinical trials
 Risk Reduction
 Prophylactic BSO
Family with Multiple Cases of Breast
and Ovarian Cancer
Br CA 63
Ov CA 50
Ov CA36
Event-Free Survival By Mutation Status
Proportion Event-Free
1.2
Mutation +
Mutation -
1
0.8
0.6
0.4
0.2
0
0
24
48
72
96
120
144
168
Months
from Robson, et al. J Clin Oncol 16:1642-1649,
1998
192
216
Second Malignancies in BRCA1/2 Carriers
Mutation carriers
No Mutation
12 contralateral BC
5 contralateral BC
3 ovarian neoplasia
0 ovarian neoplasia
1 AML
1 endometrial carcinoma
Benefit of Risk-Reducing Surgery
No
Hazards
Oophrectomy oophorectomy
ratio
Breast
21/99
60/142
0.47
cancer
(21.2%)
(41.3%)
(0.42-0.77)
Ovarian
8/259
58/282
0.04
cancer
(3.1%)
(19.9%)
(0.01-0.06)
Rebbeck, New Engl J Med. 346:1616-22,
2002
Protections Against Genetic Discrimination
NYS Insurance Law. § 2615. Genetic testing written informed consent.
“No authorized insurer or person acting on behalf of an authorized
insurer shall request or require an individual proposed for insurance
coverage to be the subject of a genetic test without receiving the
written informed consent of such individual prior to such testing, in
advance of the test.”
NYS Civil Rights Law. § 79-l. Confidentiality of records of genetic tests.
“No person shall perform a genetic test on a biological sample taken
from an individual without the prior written informed consent of
such individual.”
Americans with Disabilities Act. Prohibits discrimination against a
person who is regarded as having a disability.
Health Insurance Portability and Accountability Act. Prohibits group
health plans from using any health status-related factor, including
Support
genetic information, as a basis for denying or limiting eligibility for
GINA
coverage or for increasing premiums.
http://www.genome.gov/PolicyEthics/LegDatabase/pubMapSearch.cfm
Knowledge is power
 Sir Francis Bacon - 1597
 Religious Meditations
BRCA mutations in
Jewish Populations
Are there mutations specific to the
Jewish Population ?
MULTISITE 3 MUTATIONS
•Account for the majority of
inherited breast and ovarian cancer
in people of Ashkenazi Jewish
descent
•If there is a mutation that is
responsible for the cancer in an
Ashkenazi Jewish family,
approximately 90 % of the time it
will be one of these 3 mutations
 BRCA 1
 187delAG (185delAG)
 5385insC
 BRCA 2
 6174delT
**
de Oñate’s Expedition
 Left encampment
at Rio Conchos on
February 7, 1598
 ~129 soldiers plus
women, children,
and servants
 Arrived San Juan
(near Santa Fe)
July, 1598
Chronology
 1598: de Oñate settles
San Juan
 1609: de Paralta
founds Santa Fe
 1609 - 1680: continued
expansion
 1680: Pueblo revolt
 1693: Spanish retake
New Mexico
 1851: Beaubien
founds San Luis, CO
BRCA mutations in the San Luis
Valley Hispanic population
 19 breast and ovarian cancer patients, self-
identified as Hispanic, with San Luis Valley
ancestry
 All met American Society of Clinical Oncologists
Genetic Testing for Cancer Predisposition
Inclusion Criteria
 All denied knowledge of Jewish ancestry
 Underwent clinical DNA sequencing of BRCA1
and BRCA2 genes by Myriad Genetics Laboratory,
Inc.
San Luis Valley
BRCA1/2 Results
 10 patients tested positive for
a BRCA1 or BRCA2
mutation/variant
 6 185delAG BRCA1
mutation (5 breast cancer,
1 ovarian cancer)
 1 E1339X deleterious
mutation in BRCA1
 1 1205del56 deleterious
mutation in BRCA1
 1 D596H variant in BRCA2
 1 I2490T variant in BRCA2
185delAG BRCA1 mutation
 Found in ~1% of the Ashkenazi Jewish
population
 Other Ashkenazi Jewish mutations (5382insC
BRCA1 and 6174delT BRCA2) not seen so far
in San Luis Valley
 185delAG reported in Spanish, with AJ
haplotype (indicating a common ancestor)
Major Migrations in Jewish History
DFNB1, FMF,
G6PD, CF
BRCA1, BRCA2, FIX,
FV&VIII, LRRK2
Abraham
migrates from Ur
in the Chaldees
to Hebron in
Canaan
date
B.C.E..
1900
Destruction of
2nd Temple
Jewish
captives to
Rome
Kingdom of Assyrian
David and conquest
Solomon and exile
1500
Hebrew Exodus from
Egypt
Establishment of
Cohanim Y
lineage
1100
700
Babylonian
conquest
and exile
HEXA
300
Hasmonean
Jewish
Kingdom
Jewish Groups with Founder BRCA1/2
Mutations
Ashkenazi
Iraqi
Syrian
Kurdish
Bukharan
Iranian
Libyan
North African
Ethiopian
Habbanite
Yemeni Bene Israel
also Gypsies, U.S. Latinos
Support for Sephardic Jewish
Women and Their Families
Facing Breast Cancer
Eillene Leistner
Sharsheret
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