Genetic testing in an ethnically diverse cohort of high-risk women: a comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry.
BACKGROUND
Ten years after BRCA1 and BRCA2 were first identified as major breast cancer susceptibility genes, the spectrum of mutations and modifiers of risk among many ethnic minorities remain undefined.


OBJECTIVE
To characterize the clinical predictors, spectrum, and frequency of BRCA1 and BRCA2 mutations in an ethnically diverse high-risk clinic population and to evaluate the performance of the BRCAPRO statistical model in predicting the likelihood of a mutation.


METHODS
Comparative analysis of families (white, Ashkenazi Jewish, African American, Hispanic, Asian) with 2 or more cases of breast and/or ovarian cancer among first- and second-degree relatives. Families were identified at US sites between February 1992 and May 2003; in each family, the individual with the highest probability of being a mutation carrier was tested.


METHODS
Frequency of BRCA1 and BRCA2 mutations and area under the receiver operating characteristic curve for the BRCAPRO model.


RESULTS
The mutation spectrum was vastly different between families of African and European ancestry. Compared with non-Hispanic, non-Jewish whites, African Americans had a lower rate of deleterious BRCA1 and BRCA2 mutations but a higher rate of sequence variations (27.9% vs 46.2% and 44.2% vs 11.5%; P<.001 for overall comparison). Deleterious mutations in BRCA1 and BRCA2 were highest for Ashkenazi Jewish families (69.0%). Early age at diagnosis of breast cancer and number of first- and second-degree relatives with breast and ovarian cancer were significantly associated with an increased likelihood of carrying a BRCA1 or BRCA2 mutation. In discriminating between mutation carriers, BRCAPRO performed as well in African American families as it did in white and Jewish families, with an area under the curve of 0.77 (95% confidence interval, 0.61-0.88) for African American families and 0.70 (95% confidence interval, 0.60-0.79) for white and Jewish families combined.


CONCLUSIONS
These data support the use of BRCAPRO and genetic testing for BRCA1 and BRCA2 mutations in the management of high-risk African American families. Irrespective of ancestry, early age at diagnosis and a family history of breast and ovarian cancer are the most powerful predictors of mutation status and should be used to guide clinical decision making.
Nanda
Rita
R
Center for Clinical Cancer Genetics, Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center, Chicago, Ill 60637-1470, USA.
Schumm
L Philip
LP
Cummings
Shelly
S
Fackenthal
James D
JD
Sveen
Lise
L
Ademuyiwa
Foluso
F
Cobleigh
Melody
M
Esserman
Laura
L
Lindor
Noralane M
NM
Neuhausen
Susan L
SL
Olopade
Olufunmilayo I
OI
D000328:Adult; D001741:Black or African American / Q000235:genetics*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000208:ethnology* / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005820:Genetic Testing; D006801:Humans; D016015:Logistic Models; D015233:Models, Statistical; D009154:Mutation; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000208:ethnology* / Q000235:genetics*; D011336:Probability; D012307:Risk Factors; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics*