BRCA1/2 mutation prevalence is remarkably similar among women who undergo genetic testing, regardless of ethnicity. Here, we report ethnicity-specific mutation prevalence estimates ranging from 9.4% to 15.6%, with a pooled estimate of 12.6% for women of European (Western and Central) ancestry and 14.1% for all women of non-European ancestry (Latin American, African, Asian, Native American and Middle Eastern). Overall, recurrent mutations (prevalence >2%, including the Ashkenazi founder mutations) represented a proportionally larger fraction of the total mutations identified (as high as 45.7%) among the non-European ethnicities examined compared with women of Western European ancestry. However, despite similar mutation prevalence, testing was less frequently performed in non-European women [n=5,975(12.6%) of all women tested].
In evaluating the impact of genetic testing as a cancer prevention modality, our prevalence estimates are unique in their practical relevance. Unlike a high-risk clinic-based23
or a population-based sample19
, ours represents a referral population reflecting a diverse range of personal and familial risk factors, yet one that is also guided by clinically-relevant forces (belief systems, provider biases, and healthcare disparities). Comparatively, the strength of this study is its inclusion of all comers referred for testing, regardless of personal or family history (Nanda et al.23
studied only “high-risk” families; John et al.19
studied only women with incident breast cancer). In their study, John et al. report a positive association of BRCA1
prevalence with Hispanic ethnicity (OR1.3, 1.0-1.7) but an inverse association with Asian ethnicity (OR0.2, 0.1-0.3). We also found a high prevalence of BRCA1
mutations in Latin American women, much of it attributable to a previously described high frequency of the 187delAG mutation ( and )29
, but found a prevalence of BRCA1
mutations in Asians (12.7%) comparable to that of Europeans (12.6%). Nonetheless, it is difficult to directly compare these important findings to our own because incident ovarian cancers were not included in John et al, and only a portion (51% of high-risk, 57% of average risk) of the population was tested (and only for BRCA1
Striking racial/ethnic variability in the number of women undergoing genetic testing in the United States exists. In our sample, 87.4% of tested subjects reported European ancestry, 4.2% Latin American ancestry, 3.8% African ancestry, and 2.6% Asian ancestry (see ). Data from the US 2000 Census estimate that 74% of the US population is white (this figure includes most Hispanics, who represent 14.8% of the population), 13.4% African American, and 4.4% Asian.30
While the standard US Census racial designations are clearly different than the ancestral categories offered on the TRF, analysis of the data suggests that genetic testing for hereditary breast cancer has been performed disproportionately more often in white women.
Differences in breast and ovarian cancer epidemiology, disease biology, and healthcare access/utilization may contribute to ethnicity-specific variability in the number of women receiving genetic testing. In the United States, the incidence of both breast and ovarian cancer is higher in white women than other racial/ethnic groups.31-32
Nonetheless, breast cancer mortality for African American women exceeds that of white women, and is nearly double that of Asian American, Hispanic, and Native American counterparts.31,33
Ethnicity-specific variation in risk factor exposure,34
and reproductive/hormonal risks,40-41
may also contribute to observed differences in cancer incidence and genetic testing uptake.
There may also be inherent biologic differences in tumors among ethnic groups. African American women have a high proportion of early-onset (pre-menopausal) breast cancers, particularly those displaying basal-like and/or triple-negative histopathology.42-44
Because early-onset breast cancer is an established hereditary risk criterion, particularly for BRCA1
-related breast cancers, disease biology may in part explain the lower age observed among women of African origin in our cohort, as well as the higher proportion of BRCA1
mutations (64.3%) seen in this group.
Healthcare access and/or utilization barriers to testing must also be considered. To investigate provider-based differences in testing referral, we examined whether women of European ancestry were referred at lower thresholds by calculating the fraction of women meeting criteria for elevated risk. As seen in , absolute risk differences between ethnicities were overall minimal, on the order of only a few percentage points. Thus, in this study, those women who ultimately received BRCA1/2
testing were of comparable pre-test risk, and so potential disparities in referral thresholds or practices45
would alone be unlikely to explain the population disproportions observed. Other sources of differences in genetic testing uptake related to healthcare access/utilization have been documented and should also be considered, including ethnicity-specific socio-economic barriers (lack of health insurance46
or access to primary care47
) cultural differences (perception of risk45,48-49
or transmission of family cancer history49
), fears of genetic discrimination,50
differences in medical knowledge-base,45,47-48
and responses to genetic counseling.51
Recurrent mutations were common, with at least one of the three Ashkenazi founder mutations being identified at elevated frequency in nearly every ethnicity. While unknown or undisclosed Ashkenazi Jewish ancestry in these populations may in part explain this finding, a de novo
mutation occurring at the same site as the Ashkenazi founder 187delAG must also be considered.29,52
Among women of African ancestry, five recurrent mutations with prevalence >2% were observed. A previously described 943ins10 founder mutations in BRCA1
was the most commonly seen in our sample.53
For the Middle Eastern, Latin American, and African subgroups, recurrent mutations represented a sizable proportion of all mutations detected (45.7%, 36.6%, and 31.5%, respectively), although these numbers are small compared to the >90% of Ashkenazi Jewish individuals who have an Ashkenazi founder mutation. Extensive haplotype analysis has not been conducted to determine whether all of these represent true founder mutations (mutations sharing a common haplotype), but the low rate of de novo
mutations in the BRCA1/2
genes would suggest that most, if not all, may be traced to common ancestral origins. Though unlikely, the possibility exists that the prevalence of recurrent mutations in our dataset could be slightly inflated if two relatives independently underwent full-sequence testing. Nonetheless, it is standard practice that once a mutation has been identified, carrier status is confirmed in family members by single-site DNA analysis.
Variants of uncertain significance (VUS) were identified in 6.2% (n=2874) of subjects, excluding individuals with simultaneous deleterious mutations (n=183). Genetically distinct and/or under-tested populations will contain VUS not seen in the White/European reference population. For example persons of African ancestry have a disproportionately large number of ancient BRCA1
and have been tested at only a fraction of the frequency (see ), so their DNA sequences predictably vary from the European-influenced North American haplotypes with greater frequency. VUS reporting has declined with increased volume of testing, most notably in women of African ancestry [37% (2002)→17% (2006)]. Re-classification of the VUS reported in the current study should, however, have minor impact on reported prevalence estimates of deleterious mutations.
This work has several important limitations. As a non-probability (opportunity) sample, our study population is subject to multiple selection biases that may influence receipt of testing and therefore bias prevalence estimates. Self-reported race/ethnicity or personal/family cancer histories collected from the TRF (particularly among high-risk persons) are subject to mis-classification, imprecision (e.g. changing self-reported ethnic identity over time), and cancer history recall bias. Finally, because family structure and size are not specifically queried on the TRF, individual risk estimation using popular clinical risk assessment tools is not possible. Nonetheless, because these data reflect empirical mutation prevalence in a clinically relevant population, they remain valuable for risk assessment. Several comparative analyses of the Myriad prevalence tables to other risk assessment tools have been published in recent years.55
The exclusion of Ashkenazi Jews, though limiting our ability to directly compare findings to the other ethnicities studied here, is nonetheless essential because mutation prevalence and testing procedures (i.e. use of the founder panel) are so different for this group that a reasonable comparison cannot be made. Moreover, provider referral thresholds for testing are also very different, with several authorities recently advocating population screening of Ashkenazi women. We excluded persons reporting no ethnicity because of the inability to draw conclusions regarding shared ethnicity and its association to mutation frequency, and those reporting multiple ethnicities in an attempt to enhance the genetic homogeneity of our subgroups, thereby increasing the clinical relevance of conclusions to a subject's predominant ancestral background.
Finally, the technological challenges of diagnostic BRCA1/2
DNA testing are many, including the dynamic process of VUS detection and reclassification. More recently, multi-level testing for LGR, estimated to occur in 7-10% of sequence negative individuals with an a priori
risk of 30% or higher,56
has been implemented, improving mutation detection. However, while important at the individual level, the impact of rearrangement testing on overall mutation prevalence estimates will likely be minimal.
The identification and cloning of the BRCA1
cancer predisposition genes opened the doorway to a new era of genetics-based cancer prevention and risk assessment.9,10 BRCA1/2
mutation prevalence is high and nearly identical among women of diverse ethnicities undergoing clinical genetic testing. Nonetheless, testing volumes are disproportionately low among women from non-European ancestries, and likely reflect the complex social, economic, and cultural factors governing healthcare access and utilization. Clinical genetic testing is an integral component of hereditary breast-ovarian cancer risk assessment and should be considered in all high-risk women regardless of race and/or ethnic background.