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Breast Cancer Genetics and the Sephardic Jewish Woman Sephardic Community Center March 26, 2008 PowerPoint Presentation
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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.

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Breast Cancer Genetics and the Sephardic Jewish Woman Sephardic Community Center March 26, 2008

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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
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
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
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
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
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
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
Risk Factors for Breast Cancer

Personal history of breast cancer


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


family history and 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 basis of cancer 5 6 hits in the tumor cell dna
Genetic Basis of Cancer5-6 Hits in the Tumor Cell DNA

Risk Factors



Dietary carcinogens

Heritable mutations

Chromosomal loss or


Somatic mutations

what is the evidence for a hereditary predisposition to cancer twin studies
What is the Evidence for aHereditary Predisposition to Cancer?Twin Studies

Concordance rates %








Colorectum (men)



Colorectum (women)














Lichtenstein P. N Engl J Med. 343:78-85, 2000

factors suggestive of hereditary cancer

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

percentage of cancer that is hereditary
Percentage of Cancer that is Hereditary

Jemal, et al, Cancer 2004. CA Cancer J Clin 2004; 54:8-29

breast cancer risk estimates based on family history
Breast Cancer Risk Estimates Based on Family History

Affected relative

Age of affected relative

Cumulative risk (%) by age 80

One first degree





Two second degree





Two first degree

Both < 50


Both >50


Two second degree

Both < 50


Both > 50


Hoskins, et al. JAMA273:577, 1995, adapted from Claus et al. Cancer 73:643, 1994

inherited susceptibility to breast cancer
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)
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
Presumed Effects of Heritable BRCA1 and BRCA2 Mutations

DNA damage



Normal BRCA1 or BRCA2

failed DNA repair

DNA repair

Normal p53

p53 mutation


cell death

does everyone with a brca mutation develop 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.

hereditary breast ovarian cancer syndrome brca1 brca2
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 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?
  • 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
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
who should consider genetic testing for brca mutations
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
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
How Do We Use the Information: Increased Surveillance

Breast cancer Self-exam



Colon cancer Colonoscopy

Ovarian cancer Ultrasound


Prostate cancer Digital exam



breast cancer surveillance
Breast Cancer Surveillance
  • Screening
  • Diagnosis
  • Monitor for recurrence
  • Watch for contralateral breast


  • Techniques
    • Self Exam
    • Physician Exam
    • Mammogram
    • Ultrasound
    • MRI
how do we use the information risk reducing surgery or chemoprevention
How Do We Use the Information: Risk-Reducing Surgery or Chemoprevention?

Breast cancer Hormonal manipulation

Prophylactic mastectomy

Colon cancer Diet


Total colectomy

Ovarian cancer Hormonal manipulation

Prophylactic oophrectomy

Prostate cancer Hormonal manipulation


ovarian cancer screening and prevention
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
event free survival by mutation status
Event-Free Survival By Mutation Status

from Robson, et al. J Clin Oncol 16:1642-1649, 1998

second malignancies in brca1 2 carriers
Second Malignancies in BRCA1/2 Carriers

Mutation carriers

12 contralateral BC

3 ovarian neoplasia


No Mutation

5 contralateral BC

0 ovarian neoplasia

1 endometrial carcinoma

benefit of risk reducing surgery
Benefit of Risk-Reducing Surgery

Rebbeck, New Engl J Med. 346:1616-22, 2002

protections against genetic discrimination
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.



knowledge is power
Knowledge is power

Sir Francis Bacon - 1597

Religious Meditations

are there mutations specific to the jewish population
Are there mutations specific to the Jewish Population ?


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 o ate s expedition
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


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
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
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
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
Major Migrations in Jewish History








Destruction of 2nd Temple

Jewish captives to Rome



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 ofCohanim Y lineage


jewish groups with founder brca1 2 mutations
Jewish Groups with Founder BRCA1/2 Mutations








North African


Bene Israel



also Gypsies, U.S. Latinos


Support for Sephardic Jewish Women and Their Families Facing Breast Cancer

Eillene Leistner




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


Individual and group support for

women with advanced stage or

metastatic breast cancer.


Genetics for Life Program

Support and information addressing

the issues and concerns related to hereditary breast cancer.


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.

Family Focus Program

Information, resources, and

“Ask Sharsheret Hotline” to

help caregivers and

family members through

diagnosis, treatment, and beyond.


Education and Outreach

  • Medical Symposia on issues unique to young women facing breast cancer.
  • Sharsheret Supports, a national model for local support groups.

For More Information

About Sharsheret

  • Call: (866) 474-277
  • Visit:
  • E-mail:

Questions and Answers

Moderated by

Elana Silber, Sharsheret


Thank You

Sharsheret is grateful for the support of the following Symposium Sponsors:


For More Information

About Sharsheret

  • Call: (866) 474-277
  • Visit:
  • E-mail: