BRCA Founder Mutations Ashkenazi Jewish (Hungarian and Russian): - - PDF document

A high frequency of a specific gene mutation in a A high frequency of a specific gene mutation in a population founded by a small ancestral group population founded by a small ancestral group

Generations Generations later later

Development of a Founder Mutation Development of a Founder Mutation

Original Original population population Marked population Marked population decrease, migration, decrease, migration,

• r isolation
• r isolation

BRCA Founder Mutations

• Ashkenazi Jewish (Hungarian and Russian):

BRCA1 - 185delAG and 5382insC BRCA2 - 6174delT

• Icelandic:

BRCA1 G5193A BRCA2 999del5

• Finnish: BRCA1 IVS1-2A=>G
• Dutch: BRCA1 large deletions
• Norwegian: BRCA1 1675delA and 1135insA
• Scottish/Irish: BRCA1 2800delAA

Within these populations carriers share a common haplotype supporting a single ancient mutation rather than mutational hot spots

BRCA1 and BRCA2

• Estimated carriers of a deleterious mutation

1 per 1,000

• Breast cancer risk 35% – 80% by age 80

depending upon study population

• Ovarian cancer risk 20% - 40% by age 80
• Founder mutations have been identified in:

Icelanders Ashkenazi Fins African

BRCA1 and BRCA2 Mutations in the Ashkenazi Jewish Population

An estimated 1 in 40 Ashkenazi Jews An estimated 1 in 40 Ashkenazi Jews carries a carries a BRCA1 BRCA1 or

• r BRCA2

BRCA2 mutation mutation

Roa Roa BB et al. BB et al. Nat Genet Nat Genet 14:185, 1996 14:185, 1996 Oddoux Oddoux C et al. C et al. Nat Genet Nat Genet 14:188, 1996 14:188, 1996 Struewing Struewing JP.

• JP. N

N Engl Engl J Med J Med 336:1401, 1997 336:1401, 1997

185delAG 185delAG Prevalence = ~1% Prevalence = ~1% 5382insC 5382insC Prevalence = ~0.15% Prevalence = ~0.15% 6174delT 6174delT Prevalence = ~1.5% Prevalence = ~1.5%

BRCA1 BRCA1 BRCA2 BRCA2

Risks and Limitations Risks and Limitations

• Does not detect

Does not detect all all mutations mutations

• Continued risk of

Continued risk of sporadic cancer sporadic cancer

• Efficacy of interventions

Efficacy of interventions unproven unproven

• May result in

May result in psychosocial psychosocial

• r economic harm
• r economic harm

Benefits, Risks, and Limitations Benefits, Risks, and Limitations

• f BRCA Testing
• f BRCA Testing

Benefits Benefits

• Identifies high

Identifies high-

• risk

risk individuals individuals

• Identifies non

Identifies non-

• carriers in families

carriers in families with a known mutation with a known mutation

• Allows early

Allows early detection and detection and prevention strategies prevention strategies

• May relieve anxiety

May relieve anxiety

Familial Clustering of Cancer

Family history among blood relatives may reflect:

• Presence of a single inherited genetic risk [APC]
• Multiple genetic factors [BRCA + ATM]
• Inheritance of genetic markers of metabolism
• Shared environmental factors with/without

inheritance of susceptibility [tobacco smoke]

• Culturally transmitted risk factors [reproductive

decisions, hormone use]

• Multiple cases in some families may be due to:

inherited susceptibility, environmental exposures, lifestyle, reproductive patterns, health behaviors, etc

• Understanding these causal patterns will assist in defining

avenues for prevention and optimum treatment.

• Data and biospecimens from family members are essential for genetic

and environmental studies

• A confidential centralized data repository with DNA samples is

required for groundbreaking research

Genetic Epidemiology

• Cost of counseling & testing
• Concerns about health & life insurance
• Confidentiality of test results
• Family dynamics
• Barriers to screening/testing

(financial/psychological)

• Clinical decision-making: a burden for

mutation carriers

• Unresolved grief
• Survivor guilt among non-carriers
• Patient/physician/counselor communication

Factors Affecting Genetic Testing Decisions

Disparities in Genetic Testing

• African American women have been less likely to receive genetic

counseling and testing than Caucasian women OR 0.3 [0.1 -0.9]

• Myriad Genetics: among the first 10,000 individuals tested for BRCA

mutations, <10% were from under-represented racial/ethnic subgroups

• Access and knowledge increases use of genetic testing to wealthy,

well-insured and medically well informed populations.

• To correct disparities genetic services must be racially and culturally

tailored to meet the needs of specific populations

• Federally –funded low cost preventive health programs are needed

to provide reliable estimates of inherited risks & genetic penetrance

Hall MJ, Olopade OI. JCO 2006;24:

Factors potentially contributing to low acceptance of genetic services by some racial/ethnic populations:

• Limited communication among family members restricting awareness
• f diseases diagnosed among relatives
• Inaccurate personal assessment of disease risk
• Lack of knowledge of inherited risk in predicting future disease
• Inadequate understanding of the value of genetic counseling & testing
• Highly technical genetic services may not be available in local setting
• Distrust of risk reduction interventions coupled with greater

reliance on religion

Hall MJ, Olopade OI. JCO 2006;24

Disparities in Genetic Testing

Risk Models May Be Inadequate for Some Racial/Ethnic Groups

• Predictive statistical models using family history have

been developed primarily with data from white families & may not be applicable to diverse populations

• Models are based upon accurate estimates of population- specific

prevalence of high-risk genotypes – data not available for most minority populations due to limited genetic testing

• Heterogeneity within African American and other minority

populations may also complicate estimates

Concerns Associated with Genetic Testing

• Fears of genetic discrimination by employer or insurance

company

• High cost if self pay considered
• Confidentiality of genetic results in medical records &/or

among relatives

• Limited laws protecting genetic information
• Fear of recommended screening methods & their frequency
• Distrust/distaste for preventive medications or surgery
• Potential need for psychological assessment and support not

covered by health insurance

Breast-Ovarian Ashkenazi Family

Mother & Daughter with 5382insC

41 Br 34 Ov 59

Ov 70

Br 34,39 Ov 58 Br 80 Br 70 Br 32 Stomach 50

88

64 Br 36,43 Ov 59 5382insC

65

36 5382insC

Family 5-37

65

34 No Mutation

Environment Environment Exposures Exposures Genetic Factors Genetic Factors

Affected Affected

Manipulation of environmental exposures can modify risk of developing breast cancer

Racial & Ethnic Differences May Impact Inherited Factors & Environmental Exposures

Br 57 Breast 66 Ovarian 54 83 84 Br 34 32 56 55 Br 50 35

Paired Sisters Discordant for Breast Cancer Resource for Gene-Environment Studies

NY Registry: 450 families with one or more discordant sister sets including 120 BRCA carrier families

DNA Repair Capacity in Paired Sisters Discordant for Breast Cancer

• % DNA repair capacity of lymphoblastoid cell lines derived from

samples donated by 158 case and 154 control sisters from 137 NY Registry families

• Conditional logistic regression controlled for potential

confounding due to age at blood donation, body mass index, and smoking

• Mean repair capacity was lower in sisters with breast cancer

compared to unaffected siblings [difference=8.6,95% CI 4.3,13.8] 56

Breast 72 84

Br 50

Kennedy etal. JNCI 2005;97:127-32