Breast Cancer Genetics in the Jewish Population

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

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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

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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

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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

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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

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Family history as a Risk Factor for Breast Cancer
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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

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Genetic mutations contribute to cancer development
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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
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What is the Evidence for a Hereditary
Predisposition to Cancer?Twin Studies
Concordance rates
DZ
MZ
gt
Hereditary
Breast
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14
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9
Colorectum (men)
?
Environmental
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16
Colorectum (women)
1
5
Ovary
Dizygotic twins
Monozygotic twins
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Prostate
Lichtenstein P. N Engl J Med. 34378-85, 2000
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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

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Percentage of Cancer that is Hereditary
Jemal, et al, Cancer 2004. CA Cancer J Clin 2004
548-29
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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
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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)

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Genes Conferring High Risk for Breast and Ovarian
Cancer
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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

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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
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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.

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BRCA GENES Patterns of Inheritance

• Family Tree

• Pedigree

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

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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

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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

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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

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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

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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

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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

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Breast Cancer Surveillance

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

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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

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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

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Family with Multiple Cases of Breast and Ovarian
Cancer
Ov CA 50
Br CA 63
Ov CA36
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Event-Free Survival By Mutation Status
from Robson, et al. J Clin Oncol 161642-1649,
1998
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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

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Benefit of Risk-Reducing Surgery
Rebbeck, New Engl J Med. 3461616-22, 2002
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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
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Knowledge is power

• Sir Francis Bacon - 1597
• Religious Meditations

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BRCA mutations in Jewish Populations
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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

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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

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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

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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.

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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

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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)

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What about Sephardic Populations ?
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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
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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
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Support for Sephardic Jewish Women and Their
Families Facing Breast Cancer
Eillene Leistner Sharsheret
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About Sharsheret

• National Link Program
• Education and Outreach
• Quality of Life Programs

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Embrace Program
Individual and group support for women with
advanced stage or metastatic breast cancer.
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Genetics for Life Program
Support and information addressing the issues
and concerns related to hereditary breast
cancer.
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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.

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

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