BRCA1/2 Mutation Testing and Breast/Ovarian Cancer in the Ashkenazi Jewish Population

Glenn E Palomaki, B.S.

Foundation for Blood Research

Scarborough, Maine

(207) 883-4131

palomaki@fbr.org

p (1,000,000)Cumulative incidence (N) =

cs (cf)

CF = Carrier Frequency (carrier rate as a percentage)

CS = Clinical sensitivity (%)

P = Penetrance (%)

Use consensus estimates/ranges for each variable.

Integrated Approach

Carrier Rate

The rate of three founder BRCA1/2 mutation carriers among the Ashkenazi Jewish population

6174delT (BRCA2) All three combined

5382insC (BRCA1)

185delAG (BRCA1)

1 in 66 to 1 in 111

1 in 33 to 1 in 561 in 33 to 1 in 56

1 in 250 to 1 in 833

1 in 92 to 1 in 130

Fodor et al., 1998; Hartge et al., 1999; Oddoux et al., 1996; Roa et al., 1996; Struewing et al., 1995; Struewing et al., 1997.

Clinical Sensitivity

At any age

7 to 12 %7 to 12 %

Proportion of Ashkenazi Jewish women with breast cancer at any age carrying a BRCA1/2 mutation

Fodor et al., 1998; Hartge et al., 1999; Oddoux et al., 1996; Roa et al., 1996; Struewing et al., 1995; Struewing et al., 1997.

Penetrance

Proportion of Ashkenazi Jewish women with a founder mutation that develops cancer by age 70

30 to 70%30 to 70%

BRCA1 & BRCA2(weighted average)

26 to 74%BRCA2 alone

36 to 69%BRCA1 alone

Warner et al., 1999; Satagopan et al., 2001; King et al., 2003; Fodor et al., 1998; Struewing et al., 1997; Moslehi et al, 2000.

Cumulative Incidence

Caucasian Women

10.1%10.1%

Proportion of Ashkenazi Jewish women that will develop breast cancer by age 70

DevCan Software: Probability of developing or dying of cancer. Version 5.1: Statistical Research and Application Branch, National Cancer Institute; 2003.

Ashkenazi Jewish women similar?

Cumulative Incidence of Breast Cancer by Age 70

(Among Ashkenazi Jewish women using a carrier rate of 1 in 40)

121110987Penetrance (%)

70

60

50

40

30

Yellow indicates combinations with cumulative incidences within 10% of the overall rate for Caucasians

146,000159,000175,000194,000219,000250,000

125,000136,000150,000167,000188,000214,000

104,000114,000125,000139,000156,000179,000

83,00091,000100,000111,000125,000143,000

62,00068,00075,00083,00094,000107,000

Clinical Sensitivity (%)

Breast and Ovarian Cancer Risks due to Inherited Mutations in BRCA1 and BRCA2

(Mary-Claire King et al., Science, Oct 2003)

• Studied a cohort of 1,008 Ashkenazi women with breast cancer (index cases), regardless of family history

• Family members of those carrying a mutation were genotyped and cancer history collected

• Reported that– half of all mutation carriers had no family history– clinical sensitivity is 10.3%– 2.5% of Ashkenazi Jewish women carry a mutation– the BRCA1/2 penetrance to age 70 is 71%

1,000,000 followed age 20 to age 70

25,000 (2.5%) have a BRCA1/2 mutation

975,000 do not have a BRCA1/2 mutation

159,750 develop cancer

815,240 do not

develop cancer 71% develop

cancer (17,750)7,250 do not

develop cancer

Evaluate Finding Using the Integrated Approach

Cumulative Incidence is 177,500 - 80% higher than the rate expected in Caucasians

Comparison of Three Studies of Breast Cancer in Ashkenazi Jewish Women

Component King Warner Satagopan

Clin Sensitivity 10.3% 11.6% 10.1%

Penetrance (by 70) 71% 50% 40%

Carrier Rate -- assumed to be 1:40 --

CumulativeIncidence* 178,000 104,000 100,000

* Computed cumulative incidence per million women by age 70. In Caucasian women, the SEER rate is 96,000.

Acknowledgments

• Work was supported by a cooperative agreement with the CDC, Office of Genomics and Disease Prevention (CCU319352)

• Background information collected as part of an ACCE Review: Breast/Ovarian Cancer and BRCA1/2 Mutations (available on the CDC website)