Characterization of BRCA1 and BRCA2 mutations in a large United States sample.
OBJECTIVE
An accurate evaluation of the penetrance of BRCA1 and BRCA2 mutations is essential to the identification and clinical management of families at high risk of breast and ovarian cancer. Existing studies have focused on Ashkenazi Jews (AJ) or on families from outside the United States. In this article, we consider the US population using the largest US-based cohort to date of both AJ and non-AJ families.


METHODS
We collected 676 AJ families and 1,272 families of other ethnicities through the Cancer Genetics Network. Two hundred eighty-two AJ families were population based, whereas the remainder was collected through counseling clinics. We used a retrospective likelihood approach to correct for bias induced by oversampling of participants with a positive family history. Our approach takes full advantage of detailed family history information and the Mendelian transmission of mutated alleles in the family.


RESULTS
In the US population, the estimated cumulative breast cancer risk at age 70 years was 0.46 (95% CI, 0.39 to 0.54) in BRCA1 carriers and 0.43 (95% CI, 0.36 to 0.51) in BRCA2 carriers, whereas ovarian cancer risk was 0.39 (95% CI, 0.30 to 0.50) in BRCA1 carriers and 0.22 (95% CI, 0.14 to 0.32) in BRCA2 carriers. We also reported the prospective risks of developing cancer for cancer-free carriers in 10-year age intervals. We noted a rapid decrease in the relative risk of breast cancer with age and derived its implication for genetic counseling.


CONCLUSIONS
The penetrance of BRCA mutations in the United States is largely consistent with previous studies on Western populations given the large CIs on existing estimates. However, the absolute cumulative risks are on the lower end of the spectrum.
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. sichen@jhsph.edu
Sining
S
Chen
Edwin S
ES
Iversen
Tara
T
Friebel
Dianne
D
Finkelstein
Barbara L
BL
Weber
Andrea
A
Eisen
Leif E
LE
Peterson
Joellen M
JM
Schildkraut
Claudine
C
Isaacs
Beth N
BN
Peshkin
Camille
C
Corio
Leoni
L
Leondaridis
Gail
G
Tomlinson
Debra
D
Dutson
Rich
R
Kerber
Christopher I
CI
Amos
Louise C
LC
Strong
Donald A
DA
Berry
David M
DM
Euhus
Giovanni
G
Parmigiani
D000328:Adult; D000367:Age Factors; D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D007585:Jews / Q000706:statistics & numerical data; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics*; D019683:Penetrance; D012189:Retrospective Studies; D018570:Risk Assessment / Q000379:methods; D014481:United States / Q000453:epidemiology