Context 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.
Objectives 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.
Design, Setting, and Participants 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.
Main Outcome Measures 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.
Mammography beginning at age 40 years has been the mainstay of screening
for breast cancer in the United States for many years. Given the recent advances
in our understanding of breast cancer risk factors and the promise of prevention,
women from high-risk families are encouraged to consider genetic testing to
quantify their risk. High-risk women are advised to begin intensive surveillance
at either 10 years younger than the earliest case of breast cancer in the
family or at age 25 years, consider risk-reducing prophylactic surgery, and
undergo screening magnetic resonance imaging of the breast.1-4
An estimated 5% to 10% of breast cancer cases arise in individuals with
inherited mutations in autosomal dominant, highly penetrant breast cancer
susceptibility genes.5 Although the proportion
of cases due to a mutation in each of these genes remains to be determined,
7 genes—BRCA1, BRCA2, TP53, PTEN, CHK2, ATM, and STK11—are
known to contribute to breast cancer susceptibility.6-15 Germline
mutations in BRCA1 and BRCA2 are
by far the most common and account for 80% to 90% of families containing multiple
cases of breast and ovarian cancer.16
The proportion of breast cancer attributed to mutations in BRCA1 or BRCA2 has varied widely among different
studies and different ethnic groups. Mutations in BRCA1 are the most common in one report of non-Jewish Russian families,17 while BRCA2 mutations are
the most common in Iceland, where a single common mutation explains the majority
of inherited cancers of the breast and ovary.18 The
proportion of high-risk US families attributable to BRCA1 mutations has been reported to vary from 16% to 39%, while BRCA2 mutations account for 19% to 25% of families.19-23 It
is not known, however, if the proportions vary among blacks and whites and
if the spectrum of mutations reflects those of founder ancestors, as US families
are almost exclusively immigrants. Most studies in the United States and Canada
have included a large percentage of women of European and Ashkenazi Jewish
ancestry. Little information exists about genetic testing in other ethnic
minorities. Of note, one of the largest ethnic minorities in the United States,
the African American population, remains understudied, despite having a proportionately
higher incidence of early-onset breast cancer.
As genetic testing for breast cancer susceptibility has moved from the
research setting into the clinical arena, and with direct marketing to consumers
leading to increased awareness, more individuals are demanding genetic testing.
Despite the drawbacks of genetic testing, including high expense and inability
to detect all mutations, several professional groups have endorsed genetic
counseling and testing for high-risk women because of the potential benefits
of risk-reducing prophylactic surgery and intense surveillance.24 Unfortunately,
minority populations remain underrepresented in genetic studies. A recent
study has identified large racial disparities in the use of genetic counseling
and BRCA1 and BRCA2 testing.25,26 Many of the risk-assessment tools
used in cancer risk clinics, such as the BRCAPRO statistical model, were developed
based on mutation rates observed primarily in Ashkenazi Jewish and other white
women of European descent. Thus, the performance of BRCAPRO and other models
used in cancer risk clinics needs to be validated for use in African American
and other minority groups. Using a unique, ethnically diverse cohort of high-risk
families, we sought to characterize the clinical predictors of BRCA1 and BRCA2 mutations among high-risk
individuals of European and African ancestry, highlighting the similarities
and differences. To our knowledge, this is the first such comprehensive comparative
analysis of families evaluated in hospital-based cancer risk clinics.
Families were primarily identified through individuals who presented
to the Cancer Risk Clinic at the University of Chicago between February 1992
and May 2003. Families who presented to high-risk clinics at the Mayo Clinic,
Rush University Medical Center, and the University of California-San Francisco
and who participated in Myriad Genetics Laboratory beta testing for BRCA1 and BRCA2 mutation conducted
through the University of Chicago were also included in this analysis; recruitment
from these sites occurred between October 1996 and March 1997. All participants
were informed that their DNA samples would be used for mutation analysis,
were offered genetic counseling under protocols approved by the institutional
review board at each institution, and provided written informed consent.
Families were selected for this analysis if they fulfilled the inclusion
criteria of having 2 or more cases of breast cancer, ovarian cancer, or both
among first- and second-degree relatives. Individuals who had been tested
for a BRCA1 or BRCA2 mutation
before, or those with a family member who had previously been tested, were
excluded from this study to limit bias for mutation positivity.
Categorization of Race/Ethnicity
Individuals were categorized based on self-reported race/ethnicity.
Individuals were categorized as non-Hispanic, non-Jewish white (white); Ashkenazi
Jewish (Jewish); African American; Hispanic; or Asian. Because of the unique
spectrum and frequency of BRCA1 and BRCA2 mutations that occur in Ashkenazi Jewish individuals, these individuals
were analyzed separately from other whites when making comparisons between
ethnic groups.
Because the pedigrees of these families were consistent with a hereditary
breast and ovarian cancer syndrome, individuals were tested for mutations
in BRCA1 and BRCA2. Approximately
80% of the samples were analyzed at Myriad Genetics Laboratory using direct
DNA sequencing as previously described.27 The
remaining 20% were screened by either single-strand conformation polymorphism
(SSCP) or denaturing high-performance liquid chromatography (DHPLC) analysis,
followed by sequencing of those with variant results as previously described.28 Individuals who identified themselves as being of
Ashkenazi Jewish heritage were initially screened for the 3 common founder
mutations. Complete sequencing was performed only if the initial screening
did not detect one of these founder mutations. Naming and interpretation of
sequence analysis were performed as previously described.27 All
patients were classified as having a deleterious mutation, a variant of undetermined
significance, or no mutation.
Family history information (including incidence of breast, ovarian,
and other cancers; age at diagnosis; and relationship to the proband) was
collected and recorded by a genetic counselor. The predicted likelihood of
carrying either a BRCA1 or BRCA2 mutation was generated for each individual using BRCAPRO version 3.3.1.29
The Fisher exact test was used to compare the distributions of whites
and African Americans across the 3 mutation classifications (deleterious BRCA1 or BRCA2 mutation, sequence
variations, or no mutation). Logistic regression models were used to examine
the association between the likelihood of having a BRCA1 or BRCA2 mutation and several characteristics
of family history.30 A hierarchical approach
was used in which we first modeled the likelihood of having either mutation
and then modeled the likelihood of having a BRCA2 mutation
conditional on having 1 of the 2 mutations.31 In
both instances we started with models including the number of breast cancer
cases and the number of ovarian cancer cases in first- and second-degree relatives,
together with indicator variables distinguishing African Americans, Ashkenazi
Jews, and whites. We then added additional variables one by one (mean age
at diagnosis of breast cancer, number of cases of bilateral breast cancer,
and number of family members with both breast and ovarian cancer), noting
both the coefficient for the added variable and its effect on the coefficients
and standard errors for variables already in the model. In the case of the
model predicting the probability of either mutation, we also examined interaction
terms between the indicator variable for African Americans and the family
history variables (there were not sufficient data to do this for the model
distinguishing between BRCA1 and BRCA2). For all models, the linear specification for the continuous
covariates was checked by using smoothed plots of the partial residuals and
by introducing quadratic terms. The results of these analyses are reported
in terms of odds ratios (ie, the multiplicative change in the odds of the
outcome associated with a 1-unit change in the covariate), together with 95%
confidence intervals and P values (both based on
Wald tests) for testing the null hypothesis that the true odds ratio is 1.
Predictions of the likelihood of either mutation generated using the
BRCAPRO software were compared with the observed outcomes for African Americans
and non–African Americans separately.32,33 Families
were divided into quartiles, categories that each contained one fourth of
the sample ordered by predicted carrier probability. For each quartile, we
computed both the expected probability of a mutation (ie, the mean of the
BRCAPRO predictions for that quartile) and the observed incidence. In addition,
we computed the area under the receiver operating characteristic curve (AUROC)
via the standard nonparametric method. Using each value of the BRCAPRO predictions
as a classification cutpoint, we plotted the curve described by sensitivity
vs 1 − specificity. The AUROC was then computed using the
trapezoidal rule, and the binomial distribution was used to generate an exact
95% confidence interval.
All computations were performed using STATA release 8.2.34 All P values reported are 2-sided.
One hundred sixty families who sought risk counseling at the University
of Chicago between January 1992 and December 2003 met the eligibility criteria
for this analysis. Five families were excluded because of prior testing, and
38 (11 African American and 27 non–African American) were not tested.
A total of 117 of the 160 families (73%) from the University of Chicago who
fulfilled inclusion criteria were included in this analysis. In addition,
16 families from the Mayo Clinic, 14 from Rush University Medical Center,
and 8 from the University of California-San Francisco who participated in
Myriad Genetics laboratory BRCA1/BRCA2 beta testing
through the University of Chicago were included in this analysis. Of the 155
high-risk families, 78 (50.3%) were white; 43 (27.7%), African American; 29
(18.7%), Ashkenazi Jewish; 3 (1.9%), Hispanic; and 2 (1.3%), Asian. Complete
pedigree analysis revealed no intermarriage among first- and second-degree
relatives in any of the families. We did not observe deleterious mutations
in the 5 families of Hispanic or Asian descent, and these families were excluded
from further analysis because of the small numbers. Non–African American
families were more likely to have ovarian cancer and breast cancer, while
African American families were more likely to have only breast cancer. However,
bilateral breast cancer was more common among non–African American families
(Table 1).
Table 2 shows the prevalence of BRCA1 and BRCA2 mutations and
sequence variations in our sample. African Americans had a higher rate of
sequence variations but a lower rate of confirmed deleterious mutations in
comparison with whites (44.2% vs 11.5% and 27.9% vs 46.2%, respectively; P<.001 for overall comparison). In contrast, Ashkenazi
Jewish families had higher rates of deleterious mutations than other white
families (41.4% vs 30.8% for BRCA1 and 27.6% vs 15.4%
for BRCA2).
The spectrum of mutations observed in our cohort reflected the diverse
ethnic origins of our study population. In the Ashkenazi Jewish families,
3 common founder mutations—185delAG, 5385insC, and 6174delT—accounted
for 85% of the 20 mutations detected. One individual of Ashkenazi Jewish ancestry
had a C61G mutation, a BRCA1 mutation that has been
reported as a founder mutation in Poland.35 Conversely,
only 1 person of non-Jewish descent was found to have a mutation commonly
seen in Ashkenazi Jewish individuals, the 185delAG mutation (see Table 3). However, the haplotype for this mutation
was not the common Jewish haplotype. In the African American families, we
observed 1 African founder mutation (943ins10),36 and
2 recurrent mutations (1832del5 and 5296del4) that we have previously reported.37 A 5950delCT mutation was observed in 3 families of
German ancestry, and a C61G mutation was detected in 2 white families of German
or Austrian origin. One family of Scottish ancestry had a 2800delAA mutation,
which has been observed as a founder mutation in Scotland.38 As
shown in Table 4, 7 recurrent mutations
account for 44.1% of the 68 deleterious mutations detected. A large percentage
of the mutations represent founder mutations, reflecting the racial and ethnic
ancestries of the families.
Among all families combined, the likelihood of having either mutation
was strongly associated with several family history characteristics (Table 5). For example, each additional case of
breast cancer in first- or second-degree relatives was associated with a 62%
increase in the odds of a mutation (P = .002),
while each additional case of ovarian cancer was associated with a 146% increase
(P = .006). In addition, an increase of
just 1 year in the mean age at breast cancer diagnosis was associated with
a 10% reduction in the odds of having a mutation (P<.001).
When added to the model, neither the number of family members with both breast
and ovarian cancer nor the number with bilateral breast cancer yielded a statistically
significant effect (P = .31 and P = .35, respectively), and the coefficients for the other
variables remained largely unchanged.
Despite controlling for differences in family structure, African Americans
had nearly half the odds of having a deleterious mutation as whites (odds
ratio [OR], 0.52; 95% confidence interval [CI], 0.21-1.31), although this
difference was not statistically significant (P = .17).
Ashkenazi Jews had higher odds of a deleterious mutation than whites (OR,
5.09; 95% CI, 1.76-14.78; P = .003) (Table 5). When the model was estimated among
only the African American families, both the number of breast cancer cases
and the mean age at diagnosis showed effects similar to those shown for the
whole sample, but the estimated effect of the number of ovarian cancer cases
was much smaller and no longer statistically significant. Adding interaction
terms between African American ethnicity and each of these covariates to the
model of all families combined yielded values of P = .31
for number of breast cancer cases, P = .17
for number of ovarian cancer cases, and P = .45
for mean age at breast cancer diagnosis. Thus, the data provided no statistical
evidence of a difference between the African American families and the other
families in the effects of these covariates.
Table 6 shows results from a logistic
regression predicting the likelihood of having a BRCA2 mutation
conditional on having either mutation. Each additional case of ovarian cancer
was associated with an 85% reduction in the odds of a BRCA2 mutation (OR, 0.15; 95% CI, 0.04-0.61; P = .008),
while each additional year in the age at breast cancer diagnosis was associated
with a 21% increase in the odds of having a BRCA2 mutation
(OR, 1.21; 95% CI, 1.08-1.35; P = .001).
No statistically significant differences were observed between African American,
Ashkenazi Jewish, and white families in the likelihood of a BRCA2 mutation.
Characterization of High-Risk African American Families With Unclassified
Variants
Overall, the mean number of breast cancer cases per family differed
between the ethnic groups (African American families vs white and Jewish families),
while the mean age at diagnosis did not. The mean number of breast cancer
cases per family was 3.4 in African Americans and 4.4 in non–African
Americans (P = .01), while the mean age
at diagnosis of breast cancer was 46.2 years and 46.7 years, respectively
(P = .79). To further characterize the
43 African American families, we subdivided them into 3 groups: those with
deleterious mutations (n = 12), those with variants of undetermined
significance (n = 19), and those with no identifiable mutation (n = 12)
in BRCA1 or BRCA2. The mean
number of cases of breast cancer in the family was 3.0, 3.2, and 4.2, respectively,
while the mean age at breast cancer diagnosis in these groups was 43.6, 50.5,
and 42.0 years, respectively.
The BRCAPRO statistical model overestimated the probability of a mutation
among both the African American and non–African American families (Table 7). A closer inspection reveals that BRCAPRO
underestimates risk at the lowest levels, while overestimating it at the higher
levels. For example, BRCAPRO predicted that 38% of the African Americans would
have a mutation compared with the 28% observed. However, among those in the
lowest probability quartile, BRCAPRO predicted only a 2% mutation rate compared
with the 18% observed; in the highest quartile, BRCAPRO predicted a 96% mutation
rate as compared with the 80% observed. In terms of discriminating between
those with a mutation and those without, BRCAPRO performed as well among the
African American families as it did among the others. The AUROC (Figure) was 0.77 (95% CI, 0.61-0.88) for African
Americans and 0.70 (95% CI, 0.60-0.79) for the white and Ashkenazi Jewish
cohorts combined.
BRCA1 and BRCA2 mutations
do occur with appreciable frequency in high-risk families of African ancestry,
with 28% testing positive for a deleterious mutation in 1 of these genes,
a rate consistent with other clinic-based studies in the United States. Shih
et al39 reported that 22% of families seeking
genetic testing at the University of Michigan and the University of Pennsylvania
between 1992 and 1995 had a deleterious BRCA1 or BRCA2 mutation; Frank et al22 found
that 1720 (17.2%) of the first 10 000 individuals tested at Myriad Genetics
Laboratory had a deleterious mutation in 1 of these 2 genes. While the frequency
of confirmed deleterious mutations in the African American cohort was lower
than that observed in whites and Ashkenazi Jews, these differences were not
statistically significant when controlling for the covariates measuring family
history. Because our study was not powered to detect significant differences
in mutation frequency between these groups, larger studies are needed to further
investigate this question. Nonetheless, all families in this ethnically diverse
cohort benefited from the comprehensive risk assessment and counseling that
accompanied genetic testing.
Our data underscore the need for larger studies among minority populations
in the United States. There are documented racial/ethnic disparities in patterns
of referral to cancer risk clinics, as demonstrated in the recent article
by Armstrong et al.25 In that study, African
American women with a family history of breast or ovarian cancer were significantly
less likely to undergo genetic counseling and BRCA1/BRCA2 testing than were white women with a family history of breast or ovarian
cancer (odds ratio, 0.22; 95% CI, 0.12-0.40).
Differences in patterns of referral based on race/ethnicity might contribute
to lower rates of deleterious mutations in the African Americans in our study.
The African American families in this study had a lower incidence of ovarian
cancer than the non–African American families. While this might suggest
that the African American families referred for testing might be at lower
risk for having a BRCA1 or BRCA2 mutation, even among the families with deleterious mutations, African
American families had a lower mean number of ovarian cancer cases in first-
and second-degree relatives compared with white and Jewish families (0.29
vs 0.72). In general, African Americans have a lower incidence of ovarian
cancer compared with whites,40 and our data
suggest that even in the setting of BRCA1 or BRCA2 mutations, they have a lower rate as well. While
we cannot exclude differences in patterns of referral as the reason for the
lower rates of ovarian cancer seen in these high-risk African American women,
differences in disease modifiers across ethnic groups could also explain differences
in ovarian cancer rates. Further study of these populations matched for family
history will best address this issue.
While rates of deleterious mutations were lower among African Americans,
polymorphisms and variants of unknown significance were much more common than
in whites (44.2% vs 11.5%). A comparison with rates in Ashkenazi Jews could
not be made, as those who were found to have 1 of the 3 Ashkenazi founder
mutations did not have complete sequencing performed. The role that polymorphisms
and unclassified variants of BRCA1 and BRCA2 play in breast cancer etiology remains ill-defined. Misclassification
of deleterious mutations as unclassified variants due to paucity of sequence
information in the public database41 could
contribute to the lower rates of deleterious mutations identified among these
high-risk African American families. As demonstrated in Table 8, these families have multiple cases of breast cancer. Among
African Americans, those with no identifiable mutation in either gene had
a mean age at breast cancer diagnosis comparable with that in those families
with deleterious mutations (43.6 years and 42.0 years, respectively). There
are several possible explanations for this observation. One is that while
some ethnic groups have high rates of BRCA1 or BRCA2 mutations, African Americans have a higher rate of
mutation in another, as-yet unidentified, breast cancer susceptibility gene.
Another possibility is that African Americans have large rearrangements or
deletions, such as those that have been described in other populations.42-44 These alterations
would not have been detected by the screening methods used in our study. Furthermore,
one half of the African Americans included in our study were screened for
mutations by SSCP or DHPLC analysis. While DHPLC has a sensitivity comparable
to that of direct DNA sequencing, SSCP has a sensitivity of 72%45;
thus, we cannot exclude the possibility that some mutations might have been
missed on the few samples screened in this manner. For the 19 African American
families with sequence variations in BRCA1 and BRCA2, the mean age at diagnosis of breast cancer is older
(50.5 years) and closer to the mean age at diagnosis of sporadic breast cancer.
While this might suggest that these variants are not pathogenic, it is possible
that they represent hypomorphic alleles that contribute to increased risk
but not to the same degree as protein-truncating mutations. In a recent study
of Nigerian breast cancer patients younger than 40 years and unselected for
family history, we observed BRCA1 or BRCA2 sequence variations in 29 of 39 individuals (74%), with 69% having
sequence variations in BRCA2.46 Unfortunately,
there is a paucity of data about the genetic diversity in BRCA1 and BRCA2 in African populations or
the functional consequences of these variants. While some of these variants
might represent benign alterations, it is possible that they do contribute
to disease, thus adding to the complexity of genetic counseling in populations
of African ancestry.
The spectrum of mutations we observed in African Americans is vastly
different from what we observed in individuals of European descent. The 943ins10
founder mutation we detected in an African American woman has been traced
back to its ancient origin in the Ivory Coast in West Africa.36 The
2 recurrent mutations that we detected in African American families are also
unique to this ethnic group.37 As expected,
the 3 common Ashkenazi Jewish mutations—185delAG, 5385insC, and 6174delT—with
the exception of 1 individual, were only detected in women of Ashkenazi Jewish
heritage. Because of the small numbers of African American mutation carriers
in our cohort and the significant genetic diversity, it was not possible to
identify a panel of mutations that occur with a high frequency in African
Americans. However, we have now evaluated more than 200 individuals of African
ancestry with early-onset breast cancer and have yet to come across additional
recurrent mutations.28,37,46 Given
the genetic diversity of the African American population, it is unlikely that
screening for a panel of founder mutations will be as effective in this population
as is the case for the Ashkenazim.
Because BRCAPRO is widely used to aid in the genetic counseling process,
it is important to evaluate the performance of this statistical model in an
ethnically diverse cohort of individuals. Interestingly, the performance in
our study was similar to that reported in other recent studies. Euhus et al,47 based on a sample of 148 predominantly white and
Jewish families, estimated the AUROC for BRCAPRO to be 0.71, nearly identical
to the value observed here. Furthermore, Berry et al48 observed
that BRCAPRO both underestimated the likelihood of mutation at the lowest
levels of risk and overestimated the likelihood of mutation at the highest
levels of risk; again, just as we have observed here. The BRCAPRO model was
designed to predict the likelihood of carrying a BRCA1 or BRCA2 mutation, as opposed to the likelihood of such a
mutation being detected, and it is conceivable that our mutation detection
methods are not sensitive enough to detect all potentially deleterious mutations.
Furthermore, the BRCAPRO model only includes first- and second-degree relatives
in risk prediction, which frequently leads to an underestimation of risk,
particularly in cases in which cancer predisposition is inherited paternally.
While BRCAPRO has limitations, our data suggest that it performs as well among
African American families as it does among white and Jewish families, making
it a useful clinical risk assessment tool in African American families.
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 racial/ethnic minorities
remain undefined. Our data support the use of personal and family history
of breast cancer, ovarian cancer, or both in making clinical decisions and
identifying individuals who are likely to benefit from genetic counseling.
Certain family characteristics—most notably the number of breast cancer
cases among first- and second-degree relatives and the mean age at diagnosis
of breast cancer—are associated with the likelihood of carrying a deleterious
mutation among African Americans, as has previously been observed in white
and Ashkenazi Jewish families.
Our observations underscore the need for large, collaborative studies
to systematically validate the role of genetic testing, the use of risk prediction
models, and the role of risk-reducing strategies in improving health outcomes
for individuals of African ancestry.
Corresponding Author: Olufunmilayo I. Olopade,
MD, University of Chicago Medical Center, 5841 S Maryland Ave, MC 2115, Chicago,
IL 60637-1470 (folopade@medicine.bsd.uchicago.edu).
Author Contributions: Drs Nanda and Olopade
had full access to all of the data in the study and take responsibility for
the integrity of the data and the accuracy of the data analysis.
Study concept and design: Nanda, Olopade.
Acquisition of data: Cummings, Fackenthal,
Sveen, Cobleigh, Esserman.
Analysis and interpretation of data: Nanda,
Schumm, Ademuyiwa, Esserman, Lindor, Neuhausen, Olopade.
Drafting of the manuscript: Nanda, Schumm,
Fackenthal, Sveen, Olopade.
Critical revision of the manuscript for important
intellectual content: Nanda, Schumm, Cummings, Fackenthal, Sveen, Ademuyiwa,
Cobleigh, Esserman, Lindor, Neuhausen, Olopade.
Statistical analysis: Schumm.
Obtained funding: Olopade.
Administrative, technical, or material support:
Nanda, Cummings, Fackenthal, Sveen, Ademuyiwa, Esserman, Neuhausen.
Study supervision: Olopade.
Financial Disclosures: None reported.
Funding/Support: This study was supported by
National Cancer Institute grant R01 CA89085-01A1, the Falk Medical Research
Trust, the Breast Cancer Research Foundation, and the Entertainment Industry
Fund National Women’s Cancer Research Alliance. Dr Olopade is a Doris
Duke Distinguished Clinical Scientist; Dr Nanda is supported by a Postdoctoral
Award from the US Army Department of Defense, grant W81XWH-04-1-0545; and
Dr Neuhausen is supported by National Institutes of Health grant CA74415.
Role of the Sponsors: None of the funding organizations
had any role in the design and conduct of the study; the collection, analysis,
and interpretation of the data; or the preparation, review, or approval of
the manuscript.
Acknowledgment: We thank the staff at each
site, all of the families who participated in the study, and Myriad Genetics
Laboratory Inc, Salt Lake City, Utah.
1.Kauff ND, Satagopan JM, Robson ME.
et al. Risk-reducing salpingo-oophorectomy in women with a
BRCA1 or
BRCA2 mutation.
N Engl J Med. 2002;346:1609-161512023992
Google ScholarCrossref 2.Meijers-Heijboer H, van Geel B, van Putten WL.
et al. Breast cancer after prophylactic bilateral mastectomy in women with
a
BRCA1 or
BRCA2 mutation.
N Engl J Med. 2001;345:159-16411463009
Google ScholarCrossref 3.Rebbeck TR, Lynch HT, Neuhausen SL.
et al. Prophylactic oophorectomy in carriers of
BRCA1 or
BRCA2 mutations.
N Engl J Med. 2002;346:1616-162212023993
Google ScholarCrossref 4.Kriege M, Brekelmans CT, Boetes C.
et al. Efficacy of MRI and mammography for breast-cancer screening in women
with a familial or genetic predisposition.
N Engl J Med. 2004;351:427-43715282350
Google ScholarCrossref 5.Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The genetic attributable risk of breast and ovarian cancer.
Cancer. 1996;77:2318-23248635102
Google ScholarCrossref 6.Meijers-Heijboer H, van den Ouweland A, Klijn J.
et al. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC
in noncarriers of
BRCA1 or
BRCA2 mutations.
Nat Genet. 2002;31:55-5911967536
Google ScholarCrossref 7.Giardiello FM, Brensinger JD, Tersmette AC.
et al. Very high risk of cancer in familial Peutz-Jeghers syndrome.
Gastroenterology. 2000;119:1447-145311113065
Google ScholarCrossref 8.Miki Y, Swensen J, Shattuck-Eidens D.
et al. A strong candidate for the breast and ovarian cancer susceptibility
gene
BRCA1. Science. 1994;266:66-717545954
Google ScholarCrossref 9.Wooster R, Bignell G, Lancaster J.
et al. Identification of the breast cancer susceptibility gene
BRCA2. Nature. 1995;378:789-7928524414
Google ScholarCrossref 10.Tavtigian SV, Simard J, Rommens J.
et al. The complete
BRCA2 gene and mutations in chromosome
13q-linked kindreds.
Nat Genet. 1996;12:333-3378589730
Google ScholarCrossref 11.Li FP, Fraumeni JF Jr, Mulvihill JJ.
et al. A cancer family syndrome in twenty-four kindreds.
Cancer Res. 1988;48:5358-53623409256
Google Scholar 12.Brownstein MH, Wolf M, Bikowski JB. Cowden’s disease: a cutaneous marker of breast cancer.
Cancer. 1978;41:2393-2398657103
Google ScholarCrossref 13.Boardman LA, Thibodeau SN, Schaid DJ.
et al. Increased risk for cancer in patients with the Peutz-Jeghers syndrome.
Ann Intern Med. 1998;128:896-8999634427
Google ScholarCrossref 14.Lim W, Hearle N, Shah B.
et al. Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers
syndrome.
Br J Cancer. 2003;89:308-31312865922
Google ScholarCrossref 15.Vahteristo P, Bartkova J, Eerola H.
et al. A CHEK2 genetic variant contributing to a substantial fraction of familial
breast cancer.
Am J Hum Genet. 2002;71:432-43812094328
Google ScholarCrossref 16.Easton DF, Bishop DT, Ford D, Crockford GP.Breast Cancer Linkage Consortium. Genetic linkage analysis in familial breast and ovarian cancer: results
from 214 families.
Am J Hum Genet. 1993;52:678-7018460634
Google Scholar 17.Gayther SA, Harrington P, Russell P, Kharkevich G, Garkavtseva RF, Ponder BA. Frequently occurring germ-line mutations of the
BRCA1 gene in ovarian cancer families from Russia.
Am J Hum Genet. 1997;60:1239-12429150173
Google Scholar 18.Thorlacius S, Olafsdottir G, Tryggvadottir L.
et al. A single
BRCA2 mutation in male and female
breast cancer families from Iceland with varied cancer phenotypes.
Nat Genet. 1996;13:117-1198673089
Google ScholarCrossref 19.Schubert EL, Lee MK, Mefford HC.
et al.
BRCA2 in American families with four or more
cases of breast or ovarian cancer: recurrent and novel mutations, variable
expression, penetrance, and the possibility of families whose cancer is not
attributable to
BRCA1 or
BRCA2. Am J Hum Genet. 1997;60:1031-10409150150
Google Scholar 20.Couch FJ, DeShano ML, Blackwood MA.
et al.
BRCA1 mutations in women attending clinics
that evaluate the risk of breast cancer.
N Engl J Med. 1997;336:1409-14159145677
Google ScholarCrossref 21.Newman B, Mu H, Butler LM, Millikan RC, Moorman PG, King MC. Frequency of breast cancer attributable to
BRCA1 in a population-based series of American women.
JAMA. 1998;279:915-9219544765
Google ScholarCrossref 22.Frank TS, Deffenbaugh AM, Reid JE.
et al. Clinical characteristics of individuals with germline mutations in
BRCA1 and
BRCA2: analysis of 10,000
individuals.
J Clin Oncol. 2002;20:1480-149011896095
Google ScholarCrossref 23.Szabo CI, King MC. Population genetics of
BRCA1 and
BRCA2. Am J Hum Genet. 1997;60:1013-10209150148
Google Scholar 24.American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic
testing for cancer susceptibility.
J Clin Oncol. 2003;21:2397-240612692171
Google ScholarCrossref 25.Armstrong K, Micco E, Carney A, Stopfer J, Putt M. Racial differences in the use of
BRCA1/2 testing
among women with a family history of breast or ovarian cancer.
JAMA. 2005;293:1729-173615827311
Google ScholarCrossref 26.Hall M, Olopade OI. Confronting genetic testing disparities: knowledge is power.
JAMA. 2005;293:1783-178515827320
Google ScholarCrossref 27.Frank TS, Manley SA, Olopade OI.
et al. Sequence analysis of
BRCA1 and
BRCA2: correlation of mutations with family history and ovarian cancer
risk.
J Clin Oncol. 1998;16:2417-24259667259
Google Scholar 28.Gao Q, Tomlinson G, Das S.
et al. Prevalence of
BRCA1 and
BRCA2 mutations among clinic-based African American families with breast
cancer.
Hum Genet. 2000;107:186-19111030417
Google ScholarCrossref 30.Hosmer DW Jr, Lemeshow S. Applied Logistic Regression. 2nd ed. New York, NY: John Wiley & Sons; 2000
31.McCullagh P, Nelder JA. Generalized Linear Models. 2nd ed. New York, NY: Chapman & Hall; 1991
32.Berry DA, Parmigiani G, Sanchez J, Schildkraut J, Winer E. Probability of carrying a mutation of breast-ovarian cancer gene
BRCA1 based on family history.
J Natl Cancer Inst. 1997;89:227-2389017003
Google ScholarCrossref 33.Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities for breast cancer-susceptibility
genes
BRCA1 and
BRCA2. Am J Hum Genet. 1998;62:145-1589443863
Google ScholarCrossref 34. STATA [statistical software]. Release 8.2. College Station, Tex: Stata Corp; 2005
35.Gorski B, Byrski T, Huzarski T.
et al. Founder mutations in the
BRCA1 gene in Polish
families with breast-ovarian cancer.
Am J Hum Genet. 2000;66:1963-196810788334
Google ScholarCrossref 36.Stoppa-Lyonnet D, Laurent-Puig P, Essioux L.
et al. Institut Curie Breast Cancer Group.
BRCA1 sequence variations in 160 individuals
referred to a breast/ovarian family cancer clinic.
Am J Hum Genet. 1997;60:1021-10309150149
Google Scholar 37.Gao Q, Neuhausen S, Cummings S, Luce M, Olopade OI. Recurrent germ-line
BRCA1 mutations in extended
African American families with early-onset breast cancer.
Am J Hum Genet. 1997;60:1233-12369150171
Google Scholar 38.Liede A, Cohen B, Black DM.
et al. Evidence of a founder
BRCA1 mutation in Scotland.
Br J Cancer. 2000;82:705-71110682686
Google ScholarCrossref 39.Shih HA, Couch FJ, Nathanson KL.
et al.
BRCA1 and
BRCA2 mutation
frequency in women evaluated in a breast cancer risk evaluation clinic.
J Clin Oncol. 2002;20:994-99911844822
Google ScholarCrossref 40.National Cancer Institute. SEER*Stat Database: Incidence.
November 2003. Available at: http://www.seer.cancer.gov/.
Accessibility verified April 11, 2005 42.Unger MA, Nathanson KL, Calzone K.
et al. Screening for genomic rearrangements in families with breast and ovarian
cancer identifies
BRCA1 mutations previously missed
by conformation-sensitive gel electrophoresis or sequencing.
Am J Hum Genet. 2000;67:841-85010978226
Google ScholarCrossref 43.Montagna M, Dalla Palma M, Menin C.
et al. Genomic rearrangements account for more than one-third of the
BRCA1 mutations in northern Italian breast/ovarian cancer
families.
Hum Mol Genet. 2003;12:1055-106112700174
Google ScholarCrossref 44.Puget N, Torchard D, Serova-Sinilnikova OM.
et al. A 1-kb Alu-mediated germ-line deletion removing
BRCA1 exon 17.
Cancer Res. 1997;57:828-8319041180
Google Scholar 45.Eng C, Brody LC, Wagner TM.
et al. Interpreting epidemiological research: blinded comparison of methods
used to estimate the prevalence of inherited mutations in
BRCA1. J Med Genet. 2001;38:824-83311748305
Google ScholarCrossref 46.Fackenthal JD, Sveen L, Gao Q.
et al. Complete allelic analysis of
BRCA1 and
BRCA2 variants in young Nigerian breast cancer patients.
J Med Genet. 2005;42:276-28115744044
Google ScholarCrossref 47.Euhus DM, Smith KC, Robinson L.
et al. Pretest prediction of
BRCA1 or
BRCA2 mutation by risk counselors and the computer model BRCAPRO.
J Natl Cancer Inst. 2002;94:844-85112048272
Google ScholarCrossref 48.Berry DA, Iversen ES Jr, Gudbjartsson DF.
et al. BRCAPRO validation, sensitivity of genetic testing of
BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes.
J Clin Oncol. 2002;20:2701-271212039933
Google ScholarCrossref