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BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer
Version of Record online: 24 FEB 2009
Copyright © 2009 American Cancer Society
Volume 115, Issue 10, pages 2222–2233, 15 May 2009
How to Cite
Hall, M. J., Reid, J. E., Burbidge, L. A., Pruss, D., Deffenbaugh, A. M., Frye, C., Wenstrup, R. J., Ward, B. E., Scholl, T. A. and Noll, W. W. (2009), BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer, 115: 2222–2233. doi: 10.1002/cncr.24200
- Issue online: 28 APR 2009
- Version of Record online: 24 FEB 2009
- Manuscript Accepted: 24 OCT 2008
- Manuscript Revised: 22 OCT 2008
- Manuscript Received: 16 JUN 2008
- American Cancer Society. Grant Number: MRSG-07-232-01-CPHPS
- genetic testing;
In women at increased risk for breast and ovarian cancer, the identification of a mutation in breast cancer gene 1 (BRCA1) and BRCA2 has important implications for screening and prevention counseling. Uncertainty regarding the role of BRCA1 and BRCA2 testing in high-risk women from diverse ancestral backgrounds exists because of variability in prevalence estimates of deleterious (disease-associated) mutations in non-white populations. In this study, the authors examined the prevalence of BRCA1 and BRCA2 mutations in an ethnically diverse group of women who were referred for genetic testing.
In this cross-sectional analysis, the prevalence of BRCA1 and BRCA2 mutations was assessed in a group of non-Ashkenazi Jewish women who underwent genetic testing.
From 1996 to 2006, 46,276 women who met study criteria underwent DNA full-sequence analysis of the BRCA1 and BRCA2 genes. Deleterious mutations were identified in 12.5% of women, and recurrent deleterious mutations (prevalence >2%) were identified in all ancestral groups. Women of non-European descent were younger (mean age, 45.9 years; standard deviation [SD], 11.6 years) than European women (mean age, 50 years; SD, 11.9 years; P < .001). Women of African (15.6%; odds ratio [OR], 1.3 [95% confidence interval (95% CI), 1.1-1.5]) and Latin American (14.8%; OR, 1.2 [95% CI, 1.1-1.4]) ancestries had a significantly higher prevalence of deleterious BRCA1 and BRCA2 mutations compared with women of Western European ancestry (12.1%), primarily because of an increased prevalence of BRCA1 mutations in those 2 groups. Non-European ethnicity was associated strongly with having a variant of uncertain significance; however, reclassification decreased variant reporting (from 12.8%5.9%), and women of African ancestry experienced the largest decline (58%).
Mutation prevalence was found to be high among women who were referred for clinical BRCA1 and BRCA2 testing, and the risk was similar across diverse ethnicities. BRCA1 and BRCA2 testing is integral to cancer risk assessment in all high-risk women. Cancer 2009. © 2009 American Cancer Society.
Each year, greater than 200,000 American women are diagnosed with breast and ovarian cancer,1 and from 5% to 10% of these cancers are attributable to inherited mutations.2-5 Knowledge of personal genetic risk is increasingly important, because prevention measures have produced significant mortality reduction in high-risk women.4, 6-8 Deleterious (disease-causing) mutations in the breast cancer 1 (BRCA1) and BRCA2 (BRCA1/2) cancer predisposition genes (BRCA1; Human Genome Organization Gene Nomenclature Committee [HGNC] no. 1100; BRCA2, HGNC1101) are the principal cause of hereditary breast-ovarian cancer (HBOC).9, 10 The lifetime risk of breast cancer in mutation carriers reportedly is as high as 87%.11, 12 The risks of ovarian cancer (44% in mutation carriers by age 70 years) and contralateral breast cancer (12%-27% in mutation carriers within 5 years of breast cancer diagnosis) also are elevated.11, 13-15 In women who have a personal or family history suggestive of HBOC, BRCA1/2 full sequencing and analysis for large genomic rearrangements are used routinely to quantify the genetic component of cancer risk.
The association between race/ethnicity (hereinafter ethnicity) and the risk of BRCA1/2 mutation is controversial, potentially hampering prevention efforts in nonwhite women. Direct comparisons of mutation prevalence by ethnicity are few.16-20 Ashkenazi Jews have a markedly elevated risk of HBOC secondary to a high frequency of BRCA1/2 mutations (1 in 40 women or a 10-fold elevated risk over the general US population) mainly attributable to 3 well described founder mutations in BRCA1 (187delAG and 5385insC) and BRCA2 (6174delT).12, 21-22 For the remaining high-risk women, the ethnicity-specific prevalence of BRCA1/2 are less clearly defined.
Deleterious BRCA1/2 mutations are present in from 1 in 400 to 1 in 800 individuals in the general population.2, 11, 15 In a 2005 clinic-based study examining ethnicity-specific BRCA1/2 mutation rates, Nanda et al reported a lower frequency of deleterious mutations (27.9% vs 46.2%) in high-risk African-American families compared with white families.23 However, in a second clinic-based study of women with early onset (at age <50 years) breast cancer, similar rates of deleterious mutations were reported among African-American women and white women (both 17%).20 More recently, researchers from Northern California published estimates of BRCA1 mutation prevalence in non-Jewish white women (2.2%), Hispanic women (3.5%), African-American women (1.3%), and Asian-American women (0.5%) with breast cancer aged <65 years in a population-based study.19
The degree to which BRCA1/2 mutation frequency differs among women of diverse ethnicities has been unclear. More noteworthy, it is unknown whether ethnicity should be a consideration in BRCA1/2 risk assessment, eligibility for genetic testing, and the adoption of targeted prevention strategies. To begin to address these questions, we examined a comprehensive data repository of BRCA1/2 testing maintained by Myriad Genetic Laboratories, Inc. (Myriad) (Salt Lake City, Utah) that was amassed over 10 years and that, by our estimates, represents >95% of the entire BRCA1/2 testing experience in the US.
MATERIALS AND METHODS
The data source for this cross-sectional analysis is a clinical database supported by Myriad of individuals who are tested for mutations in the BRCA1 and BRCA2 genes. Established in 1996, the primary purpose of this database is the organization of personal and family cancer history and mutation data collected on all individuals who are tested for BRCA1 and BRCA2 mutations through Myriad. The database includes all individuals who have undergone testing, including those who receive: 1) full-sequence DNA analysis of the BRCA1/2 genes; 2) site-specific DNA testing for individuals with a known familial mutation; and 3) founder panel testing at 3 sites for 2 highly prevalent mutations in BRCA1 (187delAG and 5385insC) and a mutation in BRCA2 (6174delT), which are identified primarily in the Ashkenazi Jewish population. This database has been used in part to generate BRCA1/2 mutation prevalence estimates accessible to the public for clinical and research purposes (available at: www.myriadtests.com accessed on February 8, 2009). The structure of this database has been described previously.24
All individuals who underwent clinical full-sequence DNA testing for mutations in BRCA1/2 from November 1996 to March 2006 were considered for the study. Individuals who elect to undergo BRCA1/2 testing are referred from a wide variety of settings, ranging from private physicians' offices to high-risk cancer clinics at major academic medical centers. Demographic and personal/family cancer history data are collected directly from a test requisition form (TRF), which is included in each test kit.24 After initial receipt of the TRF, demographic and cancer history data on individuals are not updated; however, a particular test result (ie, mutation classification, such as “deleterious” or “variant of uncertain significance” [VUS]) may be updated over time and, for the current study, represents that status as of March 31, 2006. Nearly all individuals are from the US; however, a small number of international individuals (<1%) are included.
Family history data were collected from the TRF. For the purposes of this study, women who had 1) breast cancer at age <50 years, 2) ≥2 (including bilateral) breast cancers, 3) a history of ovarian cancer, or 4) both breast and ovarian cancer were considered to be at elevated risk of a BRCA1/2 mutation. Individuals with a family history of 1) breast cancer in ≥2 first-degree and/or second-degree relatives, 2) breast cancer at age <50 years in a first-degree or second-degree relative, 3) ovarian cancer in ≥2 first-degree and/or second-degree relatives, 4) breast and ovarian cancer in ≥2 first-degree and/or second-degree relatives, or 5) both breast and ovarian cancer in a single first-degree or second-degree relative also were considered to have an elevated risk of carrying a BRCA1/2 mutation.
Determination of Race/Ethnicity
Race/ethnicity was self-reported on the TRF. Traditional racial/ethnic categories (eg, “white”) were expanded for the TRF to improve the measurement of ethnogeographic variability specific to BRCA1/2 mutations. The TRF allows 8 ancestry choices: African, Ashkenazi Jewish, Asian, Central/Eastern European (hereafter referred to as Central European), Latin American/Caribbean (hereafter referred to as Latin American), Native American, Near/Middle Eastern (hereafter referred to as Middle Eastern), and Western/Northern European (hereafter referred to as Western European). An “other” option also is provided to allow individuals to write in a self-described ancestral designation. Because it is the largest subgroup, Western European ancestry serves as the referent for the majority of analyses performed here. Where indicated, individuals of Western and Central European ancestry have been combined in several analyses (referred together as European). For accuracy, racial/ethnic categorizations used by other authors (eg, “white”) are preserved later in the text; however, although they may be similar, these categories do not directly parallel our own and are introduced for comparative purposes only.
Individuals who were included in the study underwent clinical full-sequence BRCA1/2 analysis (research-related, site-specific, and founder panel testing were excluded), chose only 1 of the 8 provided ethnicity categories, were women, and completed the personal and family cancer history sections of the TRF. Individuals with incomplete personal or family cancer history were excluded. Ashkenazi Jews were excluded from this analysis, because testing procedures differ substantially in this group—most Ashkenazi women undergo initial founder mutation screening/testing and, if the test is positive, do not receive full-sequence analysis. Men were excluded because of the small numbers after excluding Ashkenazi Jews. In total, from 63,947 individuals who underwent full-sequence testing, 10,078 reported >1 ethnicity (or “other”), and 7593 had incomplete cancer histories or were men; thus, 46,276 women remained for this analysis.
Full-sequence DNA analysis of BRCA1 and BRCA2 and, since August 2002, break-point analysis for 5 large genomic rearrangements in BRCA1 (exon13del3835bp, exon13ins6kb, exon14-20del26kb, exon22del510bp, and exon8-9del7.1kb) were performed. Technical aspects of these analyses have been previously described in detail.24, 25 Mutations identified from sequence analysis were classified into 5 categories: deleterious and suspected deleterious (herein combined as “deleterious”); VUS; variant-favor polymorphism; and polymorphism.26 The deleterious classification includes all nonsense mutations and all frame-shift mutations that begin at or before the last known nonsense or frame-shift mutation shown to cosegregate with disease. In addition, specific missense mutations and noncoding intervening sequence (IVS) mutations are recognized as deleterious on the basis of data derived from linkage analysis of high-risk families, functional assays, biochemical evidence, and/or demonstration of abnormal mRNA transcript processing. “Suspected deleterious” are genetic variants for which all of the available evidence indicates a very strong likelihood that the mutation is harmful or deleterious but whose effect on protein function cannot easily be determined. A suspected deleterious result typically is treated clinically as a deleterious (mutation positive) result. Many variants initially classified as VUS have been reclassified based on additional data, using an approach similar to that described by Goldgar et al.,27 segregation analyses, and co-occurrence of known deleterious mutations with VUS in the same individual.28
The age at which individuals underwent testing was treated as a continuous variable. The mean age at the time of testing was calculated for each ethnicity and compared by using 2-sided Student t tests. Univariate analyses (with the results adjusted for age) were performed to evaluate the association of ethnicity to the presence of personal and/or familial risk factors predictive of an elevated risk of a BRCA1/2 mutation (Table 1), the prevalence of deleterious mutations, and the prevalence of VUS (Table 2). Ethnicity was treated as a dummy variable. These results are presented as odds ratios (ORs) with Western European ethnicity serving as the referent group. All confidence intervals (CIs) are reported at the 95% significance level. All statistical tests and reported P values are 2-sided (α = .05). All analyses were performed using Stata statistical software (StataCorp, College Station, Tex).
|All Individuals||Fraction at Elevated Risk*|
|Race/Ethnicity||No. (%)||No. (% of All Individuals)||OR [95% CI]†|
|Western European||36,235 (78.3)||31,588 (87.2)||Referent|
|Central European||4066 (8.8)||3464 (85.2)||0.8 [0.8-0.9]|
|Latin American||1936 (4.2)||1718 (88.7)||1.0 [0.9-1.2]|
|African||1767 (3.8)||1626 (92)||1.5 [1.2-1.8]|
|Asian||1183 (2.6)||1034 (87.4)||0.9 [0.8-1.1]|
|Native American||597 (1.3)||508 (85.1)||0.8 [0.6-1.0]|
|Middle Eastern||492 (1.1)||417 (84.8)||0.8 [0.6-1.0]|
|Total||46,276 (100)||40,355 (87.2)||—|
|No. (% Row)||VUS|
|Ethnicity||No.||BRCA1||BRCA2||Total*||OR [95% CI]†||No. (% Row)||OR [95% CI]†|
|Western European||36,235||2501 (6.9)||1899 (5.2)||4400 (12.1)||Referent||2081 (5.7)||Referent|
|Central European||4066||336 (8.3)||214 (5.3)||550 (13.5)||1.1 [1.0-1.2]||231 (5.7)||1.0 [0.9-1.1]|
|Latin American||1936||185 (9.6)||105 (5.4)||290 (14.8)||1.2 [1.1-1.4]||195 (10.1)||1.8 [1.6-2.2]|
|African||1767||180 (10.2)||100 (5.7)||280 (15.6)||1.3 [1.1-1.5]||292 (16.5)||3.2 [2.8-3.7]|
|Asian||1183||75 (6.3)||75 (6.3)||150 (12.7)||1.0 [0.9-1.2]||161 (13.6)||2.6 [2.2-3.1]|
|Native American||597||44 (7.4)||35 (5.9)||79 (13.2)||1.1 [0.9-1.4]||41 (6.9)||1.2 [0.9-1.7]|
|Middle Eastern||492||30 (6.1)||16 (3.3)||46 (9.4)||0.7 [0.5-1.0]||55 (11.2)||2.1 [1.6-2.7]|
|Total||46,276||3351 (7.2)||2444 (5.3)||5795 (12.5)||—||3057 (6.6)||—|
Ethnicity, Cancer History, and Age Characteristics
Between November 1996 and March 2006, 46,276 consecutive women who met eligibility criteria underwent BRCA1/2 testing. The racial/ethnic breakdown of the study sample is presented in Table 1. In total, 87.4% of participants (n = 40,301 women) reported European (Western or Central European) ancestry; Middle Eastern represented the smallest ethnic subgroup (n = 492; women 1.1%).
Ethnicity-specific differences in age at testing and strength of cancer history were observed. The mean age (±standard deviation) at the time of testing was 50 ± 11.9 years among European women, whereas the mean age (±standard deviation) was 45.2 ± 10.9 years for women of African descent, 48.5 ± 11.6 years for women of Native American descent, 47.1 ± 12.5 years for women of Asian descent, 44.7 ± 11.4 years for women of Latin American descent, and 47.4 ± 12.1 years for women of Middle Eastern descent (all non-Europeans, 45.9 ± 11.6 years), all of which were significantly lower (all individual P values <.001). To evaluate variability in referral thresholds, we stratified cancer history by ethnicity. The fraction of women at increased risk for a deleterious BRCA1/2 mutation secondary to a personal and/or family history of breast or ovarian cancer was higher for women of African ancestry (92%; OR, 1.5 [95% CI, 1.2-1.8]) and lower for women of Central European ancestry (85.2%; OR, 0.8 [95% CI, 0.8-0.9]) compared with women of Western European ancestry (87.2%). Ethnicity-specific frequencies of cancer history characteristics are detailed in Table 3.
|Variable||Western European, N=36,235||Central European, N=4066||Latin American, N=1936||African, N=1767||Asian, N=1183||Native American, N=597||Middle Eastern, N=492|
|Age <50 y||15,941 (44.9)||1692 (41.6)||972 (50.2)||1006 (56.9)||613 (51.8)||219 (36.7)||228 (46.3)|
|Age >50 y||6557 (18.1)||687 (16.9)||185 (9.6)||212 (12)||153 (12.9)||83 (13.9)||65 (13.2)|
|Ovarian cancer||2498 (6.9)||272 (6.7)||93 (4.8)||25 (1.4)||63 (5.3)||38 (6.4)||39 (7.9)|
|Breast and ovarian cancer||880 (2.4)||106 (2.6)||32 (1.7)||32 (1.8)||31 (2.6)||18 (3)||10 (2)|
|Bilateral breast cancer||3004 (8.3)||336 (8.3)||127 (6.6)||188 (10.6)||80 (6.8)||46 (7.7)||28 (5.7)|
|In situ breast cancer only||2497 (6.9)||334 (8.2)||139 (7.2)||116 (6.6)||108 (9.1)||47 (7.7)||29 (5.9)|
|Age <50 y||16,834 (46.5)||1833 (45.1)||965 (49.8)||1003 (56.8)||497 (42)||279 (46.7)||188 (38.2)|
|Age >50 y||11,578 (32)||1301 (32)||442 (22.8)||381 (21.6)||279 (23.6)||191 (32)||133 (27)|
|Ovarian cancer||2956 (8.2)||355 (8.7)||158 (8.2)||90 (5.1)||101 (8.5)||51 (8.5)||54 (11)|
|Breast and ovarian cancer||6267 (17.3)||702 (17.3)||324 (16.7)||271 (15.3)||134 (11.3)||96 (16.1)||68 (13.8)|
Disease-related mutations were identified in 5780 women (12.5%) (Table 2). Fifteen women carried simultaneous BRCA1 and BRCA2 mutations. Women of African ancestry had the highest prevalence of deleterious mutations (15.6%, vs 12.1% for Western European women; OR, 1.3 [95% CI, 1.1-1.5]) and had nearly twice as many BRCA1 mutations as BRCA2 mutations (180 mutations vs 100 mutations). Women of Middle Eastern descent had the lowest mutation prevalence (9.4%; OR, 0.7 [95% CI, 0.5-1.0]). Overall, BRCA1 mutations were more common than BRCA2 mutations for every ethnicity except Asians, in whom an equal frequency was observed (6.3% for each gene, 12.7% overall).
Recurrent mutations (mutation prevalence ≥2%) were identified in every ancestral subgroup (Tables 4 and 5). Some, such as the BRCA1 Ashkenazi founder mutations 187delAG and 5385insC, were identified among nearly all the ancestral groups, whereas others were unique within each group. The Ashkenazi founder mutation 187delAG was common to every ethnicity except African (range, 2.2%-15.2%), whereas the 5385insC mutation was observed in Native Americans (3.8%), Western Europeans (5.2%) and Central Europeans (14.9%). It is noteworthy that, whereas the 187delAG founder mutation is 4 to 5 times as common in Ashkenazi Jews as the 5385insC mutation, the ratio was reversed in the women of European decent who we studied: The ratio of 5385insC to 187delAG was nearly 2:1 for Western Europeans and 4:1 for Central Europeans.
|Race/Ethnicity||BRCA1||BRCA2||Observed (% of Total Mutations Identified)|
|Western European (N=4389 mutations)||5385insC||228 (5.2)|
|African (N=279 mutations)||943ins10||28 (10)|
|Central European (N=550 mutations)||5385insC||82 (14.9)|
|Native American (N=105 mutations)||187delAG||7 (6.7)|
|Asian (N=184 mutations)||L63X||6 (3.3)|
|Latin American (N=287 mutations)||187delAG||35 (12.2)|
|Middle Eastern (N=46 mutations)||187delAG||7 (15.2)|
|Rank||Location||Total No. of Mutations Identified||Ethnicities With Mutation Prevalence ≥2%|
|1||5385insC||314||Central and Western European, Native American|
|2||187delAG||204||All except African|
|3||C61G||137||Central and Western European|
Recurrent mutations also were identified within each ancestral group. The African (31.5%), Latin American (36.6%), and Middle Eastern (45.7%) subgroups had the largest percentage of total mutations by subgroup represented by recurrent mutations. In addition to the Ashkenazi founder mutations, the BRCA1 C61G mutation was identified the most often (total, 137 individuals), primarily in Europeans (Western and Central). Other than the C61G mutation and the Ashkenazi founder mutation, only the L63X mutation was found to be shared among individuals who reported different ancestral backgrounds (Middle Eastern, 7.6%; Asian, 3.3%).
Variants of Uncertain Significance
At the time of the current analysis, at least 1 mutation classified as VUS was observed in 3057 women (6.6%) who were tested (Table 2). The prevalence of VUS varied considerably by ethnicity, but VUS reporting decreased markedly, particularly for non-European subgroups, over the time of data collection because of reclassification (Fig. 1). Overall, women of African ancestry had the highest prevalence of VUS at the time of analysis (16.5%, vs 5.7% for Western European women; OR, 3.2 [95% CI, 2.8-3.7]). The prevalence of VUS was correlated inversely with the total number of individuals tested in each subgroup (P < .001 for trend).
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 pooled estimates 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 greater fraction of the total mutations identified (as high as 45.7%) among the non-European ethnicities that we examined compared with women of Western European ancestry. However, despite similar mutation prevalence, testing was performed less frequently in non-European women (n = 5975; 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 population-based sample,19 our sample represents a referral population that reflects a diverse range of personal and familial risk factors but that also is guided by clinically relevant forces (belief systems, provider biases, and healthcare disparities). Comparatively, the strength of this study is its inclusion of all individuals who were referred for testing, regardless of personal or family history (Nanda et al23 studied only “high-risk” families, and John et al19 studied only women with incident breast cancer). In their report, John et al noted a positive association of BRCA1 prevalence among Hispanics (OR, 1.3; 95% CI, 1.0-1.7) but an inverse association with Asian ethnicity (OR, 0.2; 95% CI, 0.1-0.3). We also observed a high prevalence of BRCA1 mutations among Latin American women, much of it attributable to a previously described high frequency of the 187delAG mutation (Tables 4 and 5),29 but we observed a prevalence of BRCA1/2 mutations among Asians (12.7%) comparable to that observed among Europeans (12.6%). Nonetheless, it is difficult to compare these important findings directly with our own, because incident ovarian cancers were not included in the study by John et al, only a portion of the population was tested (51% of high-risk individuals and 57% of average-risk individuals), and they were tested only for BRCA1.
Striking racial/ethnic variability exists in the number of women who undergo genetic testing in the US. In our sample, 87.4% of tested individuals reported European ancestry, 4.2% reported Latin American ancestry, 3.8% reported African ancestry, and 2.6% reported Asian ancestry (see Table 1). Data from the US 2000 Census estimate that 74% of the US population is white (this proportion includes most Hispanics, who represent 14.8% of the population), 13.4% is African American, and 4.4% is Asian.30 Although the standard US Census racial designations clearly are different from 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/use may contribute to ethnicity-specific variability in the number of women receiving genetic testing. In the US, the incidence of both breast cancer and ovarian cancer is greater among white women than among women in 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 their Asian-American, Hispanic, and Native American counterparts.31, 33 Ethnicity-specific variation in risk factor exposure,34 including dietary,35, 36 body size/weight,37, 38 behavioral,39 and reproductive/hormonal40, 41 risks also may contribute to observed differences in cancer incidence and genetic testing uptake.
There also may be inherent biologic differences in tumors among ethnic groups. African-American women have a high proportion of early onset (premenopausal) breast cancers, particularly those that display 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 explain in part the younger age observed among women of African origin in our cohort and the greater proportion of BRCA1 mutations (64.3%) observed in this group.
Healthcare access and/or use barriers to testing also must 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 that met the criteria for elevated risk. Table 1 indicates that the absolute risk differences between ethnicities overall were minimal, on the order of only a few percentage points. Thus, in this study, those women who ultimately received BRCA1/2 testing were at comparable pretest risk; thus, potential disparities in referral thresholds or practices45 alone would be unlikely to explain the population disproportions observed. Other sources of differences in genetic testing uptake related to healthcare access/use have been documented and also should be considered, including ethnicity-specific socioeconomic barriers (lack of health insurance46 or lack of 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, and at least 1 of the 3 Ashkenazi founder mutations was identified at elevated frequency in nearly every ethnicity. Although unknown or undisclosed Ashkenazi Jewish ancestry in these populations in part may explain this finding, a de novo mutation occurring at the same site as the Ashkenazi founder 187delAG also must be considered.29, 52 Among women of African ancestry, 5 recurrent mutations with prevalence ≥2% were observed. A previously described 943ins10 founder mutation in BRCA1 was the most common 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 with 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 that share 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. Although it is unlikely, the possibility exists that the prevalence of recurrent mutations in our dataset could be slightly inflated if 2 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.
We identified VUS in 6.2% of women in our study (n = 2874) excluding those who had simultaneous deleterious mutations (n = 183). Genetically distinct and/or under-tested populations will contain VUS that are not observed in the white/European reference population. For example, individuals of African ancestry have a disproportionately large number of ancient BRCA1 haplotypes54 and have been tested at only a fraction of the frequency (see Table 1); thus, predictably, their DNA sequences 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 (from 37% in 2002 to 17% in 2006). Reclassification of the VUS reported in the current study, however, should have a minor impact on reported prevalence estimates of deleterious mutations.
This work has several important limitations. Our study population, as a nonprobability (opportunity) sample, is subject to multiple selection biases that may influence the receipt of testing and, thus, may bias prevalence estimates. Self-reported race/ethnicity or personal/family cancer histories collected from the TRF (particularly among high-risk individuals) are subject to misclassification, imprecision (eg, 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 empiric mutation prevalence in a clinically relevant population, they remain valuable for risk assessment. Several comparative analyses of the Myriad prevalence tables and other risk assessment tools have been published in recent years.55
The exclusion of Ashkenazi Jews, although it limited our ability to compare findings directly with the other ethnicities that we studied, nonetheless is essential, because mutation prevalence and testing procedures (ie, 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 individuals who reported no ethnicity (because of the inability to draw conclusions regarding shared ethnicity and its association with mutation frequency) and who reported multiple ethnicities in an attempt to enhance the genetic homogeneity of our subgroups, thereby increasing the clinical relevance of conclusions to an individual's predominant ancestral background.
Finally, the technologic challenges of diagnostic BRCA1/2 DNA testing are many, including the dynamic process of VUS detection and reclassification. More recently, multilevel testing for large genomic rearrangements, which are estimated to occur in 7% to 10% of sequence-negative individuals with an a priori risk ≥30%,56 has been implemented to improve mutation detection. However, although it is important at the individual level, the impact of rearrangement testing on overall mutation prevalence estimates most likely will be minimal.
The identification and cloning of the BRCA1 and BRCA2 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 is nearly identical among women of diverse ethnicities who undergo 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 that govern healthcare access and use. 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.
Conflict of Interest Disclosures
Dr. Hall is a recipient of a Mentored Research Scholar Grant from the American Cancer Society (MRSG-07-232-01-CPHPS to M.J.H.). Dr. Hall also is a member of the Genetech Colorectal Cancer Advisory Board.
Ms. Reid and Dr. Pruss are employed by Myriad Genetics Inc. and own stock options.
Ms. Burbridge, Ms. Deffenbaugh, Ms. Frye, and Dr. Wenstrup are employed by Myriad Genetic Laboratories Inc. and own stock options.
Drs. Scholl, Ward, and Noll are former employees of Myriad Genetic Laboratories Inc. and own stock options.
- 30US Census Bureau. Overview of Race and Hispanic Ethnicity: 2000. Available at: http://www.census.gov/prod/2001pubs/ c2kbr01-1.pdf Accessed September 1, 2008.
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