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Breast Cancer Genetics in the Jewish Population

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Genes related to increased risk of breast cancer. BRCA 1. BRCA 2. ATM ... the issues and concerns related to hereditary breast cancer. Genetics for Life Program ... – PowerPoint PPT presentation

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Title: Breast Cancer Genetics in the Jewish Population


1


2
Breast Cancer Genetics and the Sephardic Jewish
Woman Sephardic Community Center March 26, 2008
3
Heredity Predisposition to Breast and Ovarian
Cancer Among Sephardic Jewish Women
Ruth Oratz, M.D. Harry Ostrer, M.D. NYU School of
Medicine
4
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.) gt150 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
5
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

6
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

7
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

8
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 cant be changed
  • Environmental
  • Behavioral - diet, exercise
  • Some factors influence risk more than others,
  • Risk for breast cancer can change over time

9
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

10
Family history as a Risk Factor for Breast Cancer
11
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

12
Genetic mutations contribute to cancer development
13
Genetic Basis of Cancer5-6 Hits in the Tumor
Cell DNA
Risk Factors Radiation Smoking Dietary
carcinogens
Heritable mutations
Chromosomal loss or rearrangement
Somatic mutations
14
What is the Evidence for a Hereditary
Predisposition to Cancer?Twin Studies
Concordance rates
DZ
MZ
gt
Hereditary
Breast
9
14
8
9
Colorectum (men)
?
Environmental
6
16
Colorectum (women)
1
5
Ovary
Dizygotic twins
Monozygotic twins
6
21
Prostate
Lichtenstein P. N Engl J Med. 34378-85, 2000
15
Factors Suggestive of Hereditary Cancer
  • 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

16
Percentage of Cancer that is Hereditary
Jemal, et al, Cancer 2004. CA Cancer J Clin 2004
548-29
17
Breast Cancer Risk Estimates Based on Family
History
Cumulative risk () by age 80
Age of affected relative
Affected relative
13-21
lt50
One first degree
9-11
gt50
10-14
lt50
Two second degree
8-9
gt50
35-48
Both lt 50
Two first degree
11-24
Both gt50
21-26
Both lt 50
Two second degree
6-16
Both gt 50
Hoskins, et al. JAMA273577, 1995, adapted from
Claus et al. Cancer 73643, 1994
18
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)

19
Genes Conferring High Risk for Breast and Ovarian
Cancer
20
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

21
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
p53 mutation
cancer
cell death
22
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.

23
BRCA GENES Patterns of Inheritance
  • Family Tree
  • Pedigree

24
Family with Multiple Cases of Breast and Ovarian
Cancer
Ov CA
Ov CA 50
Br CA 63
Ov CA36
25
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

26
BRCA mutations
  • 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
  • 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

27
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

28
Genetic Counseling for Cancer Risk Who Should Be
Tested?
  • Test the proband first.
  • If positive, offer testing to other family
    members
  • Do not recommend screening or random testing

29
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

30
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

31
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

32
Breast Cancer Surveillance
  • Screening
  • Diagnosis
  • Monitor for recurrence
  • Watch for contralateral breast
  • cancer
  • Techniques
  • Self Exam
  • Physician Exam
  • Mammogram
  • Ultrasound
  • MRI

33
How Do We Use the Information Risk-Reducing
Surgery or Chemoprevention?
Breast cancer Hormonal manipulation Prophylactic
mastectomy Colon cancer Diet Aspirin/NSAID T
otal colectomy Ovarian cancer Hormonal
manipulation Prophylactic oophrectomy Prostate
cancer Hormonal manipulation Diet

34
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

35
Family with Multiple Cases of Breast and Ovarian
Cancer
Ov CA 50
Br CA 63
Ov CA36
36
Event-Free Survival By Mutation Status
from Robson, et al. J Clin Oncol 161642-1649,
1998
37
Second Malignancies in BRCA1/2 Carriers
  • Mutation carriers
  • 12 contralateral BC
  • 3 ovarian neoplasia
  • 1 AML
  • No Mutation
  • 5 contralateral BC
  • 0 ovarian neoplasia
  • 1 endometrial carcinoma

38
Benefit of Risk-Reducing Surgery
Rebbeck, New Engl J Med. 3461616-22, 2002
39
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 genetic
    information, as a basis for denying or limiting
    eligibility for coverage or for increasing
    premiums.

Support GINA
http//www.genome.gov/PolicyEthics/LegDatabase/pub
MapSearch.cfm
40
Knowledge is power
  • Sir Francis Bacon - 1597
  • Religious Meditations

41
BRCA mutations in Jewish Populations
42
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

43


44
de Oñates 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

45
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

46
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.

47
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

48
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)

49
What about Sephardic Populations ?
50
Major Migrations in Jewish History
Destruction of 2nd Temple Jewish captives to Rome
DFNB1, FMF, G6PD, CF
BRCA1, BRCA2, FIX, FVVIII, LRRK2
Abraham migrates from Ur in the Chaldees to
Hebron in Canaan
Kingdom of David and Solomon
Assyrian conquest and exile
Hebrew Exodus from Egypt
Babylonian conquest and exile
Hasmonean Jewish Kingdom
Establishment of Cohanim Y lineage
HEXA
51
Jewish Groups with Founder BRCA1/2 Mutations
Ashkenazi
Iraqi
Bukharan
Kurdish
Syrian
Iranian
Libyan
North African
Habbanite
Bene Israel
Ethiopian
Yemeni
also Gypsies, U.S. Latinos
52
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53
Support for Sephardic Jewish Women and Their
Families Facing Breast Cancer
Eillene Leistner Sharsheret
54
About Sharsheret
  • National Link Program
  • Education and Outreach
  • Quality of Life Programs

55
Embrace Program
Individual and group support for women with
advanced stage or metastatic breast cancer.
56
Genetics for Life Program
Support and information addressing the issues
and concerns related to hereditary breast
cancer.
57
Quality of Life Programs
  • Busy Box for parents with young children facing
    breast cancer.
  • Best Face Forward to address the cosmetic side
    effects of chemotherapy and radiation treatment.

58
Family Focus Program
Information, resources, and Ask Sharsheret
Hotline to help caregivers and family members
through diagnosis, treatment, and beyond.
59
Education and Outreach
Medical Symposia on issues unique to young women
facing breast cancer. Sharsheret Supports, a
national model for local support groups.
60
For More Information About Sharsheret
Call (866) 474-277 Visit www.sharsheret.org E
-mail info_at_sharsheret.org
61
Questions and Answers
Moderated by Elana Silber, Sharsheret
62
Thank You

Sharsheret is grateful for the support of the
following Symposium Sponsors
63
For More Information About Sharsheret
Call (866) 474-277 Visit www.sharsheret.org E
-mail info_at_sharsheret.org
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