An overview of the state of genetic testing for BRCA1 and BRCA2 genes was presented at the Summit Meeting on Breast Cancer Among African American women.
An overview of the state of genetic testing for BRCA1 and BRCA2 genes was presented at the Summit Meeting on Breast Cancer Among African American women.
An exhaustive literature search was performed using PubMed and abstracts published from meetings of the American Association for Cancer Research, the American Society of Human Genetics, and the American Society of Clinical Oncology. The Breast Cancer Information Core was also searched for information regarding sequence variants in which the ethnicity of the individual tested was known.
Of the 26 distinct BRCA1 pathogenic mutations (protein-truncating, disease-associated missense, and splice variants) detected in Africans or African Americans, 15 (58%) have not been previously reported. In addition, 18 deleterious BRCA2 mutations have been identified and 10 (56%) of these are unique to the group. Only two pathogenic BRCA1 mutations (943ins10 and M1775R) have been detected in three or more unrelated families. However, seven additional BRCA1 or BRCA2 deleterious mutations have been reported in at least two unrelated families. Three of these recurrent BRCA1 mutations (943ins10, 1832del5, and 5296del4) have been characterized by haplotype studies and each likely arose from a common ancestor, including one ancestor that could be traced to the Ivory Coast in West Africa. Although only a few African-American families have been tested for BRCA1 and BRCA2 mutations, the probability of finding a mutation is invariably dependent on the age of onset and the number of breast and/or ovarian cancer cases in the family. The psychosocial implications of genetic testing for African Americans have not been well studied, so that high-risk African Americans may underestimate their risks of breast and ovarian cancer.
Deleterious BRCA1 and BRCA2 mutations have been identified in African-American and African families. A number of unique mutations have been described, but recurrent mutations are widely dispersed and are not readily identifiable in the few families that have been tested. Access to genetic counseling and testing in a culturally sensitive research setting must remain a high priority before genetic testing can be disseminated in the community. Cancer 2003;97(1 Suppl):236–45. © 2003 American Cancer Society.
The breast cancer mortality rate is high among young African-American women. A clear understanding of associated risk factors will likely lead to the development of novel interventions to prevent breast cancer and drastically reduce mortality from the disease. One of the most promising areas of research is the identification of genes, gene–environment, or gene–gene interactions that lead to increased breast cancer risk among young African-American women. Estimates from population-based studies suggest that about 3–8% of breast cancers are explained by germline mutations in highly penetrant susceptibility genes such as BRCA1 and BRCA2. Genetic testing for BRCA1 and BRCA2 has become a reality, moving from the research setting into clinical practice. This study reviews the state of the technology for African-American women and identifies opportunities for research into the genetic bases of breast cancer in this group of women.
Information was gathered from searching (through February 2001) PubMed, the Breast Cancer Information Core (BIC), and abstracts published from meetings of the American Association for Cancer Research, the American Society of Human Genetics, and the American Society of Clinical Oncology (ASC).
There may be striking similarities between BRCA1-related breast cancers and breast cancers that occur in young African-American women. For example, BRCA1-associated breast cancers occur at an earlier average age (44 years) than sporadic breast cancers.1, 2 and it has been observed that African-American patients 30–49 years of age have a greater breast cancer incidence than whites.3 Compared with noncarriers, BRCA1-associated breast cancers have higher than expected frequencies of medullary or atypical medullary carcinoma, are poorly differentiated (high tumor grade), are aneuploid with high S-phase fraction, are hormone receptor negative, and have a high frequency of p53 mutations.2, 4–9 In contrast to BRCA1, BRCA2 tumors are better differentiated with more tubular and lobular features and a higher rate of hormone receptor positivity.2, 6 Tumors in young African-American women are also more likely to be poorly differentiated and hormone receptor negative and to exhibit high nuclear grade and S-phase fraction,9, 10 A significant proportion of breast cancers in African-American women also exhibit medullary or atypical medullary features.10 These facts suggest that BRCA1 mutations may contribute to breast cancer in a significant proportion of African-American women, but limited data are available from this population to evaluate this possibility.
Hereditary breast cancer accounts for 3–8% of all breast cancers.11, 12 The highly penetrant breast cancer susceptibility genes, BRCA1 and BRCA2, contribute to an ill-defined proportion of hereditary breast cancer cases.13–16 An additional breast cancer susceptibility locus has been mapped to a region on chromosome 13.17 BRCA1 and BRCA2 may function in double-strand DNA repair, homologous recombination, transcription regulation, embryonic growth, and cell cycle regulation.18 Deleterious BRCA mutations, such as protein-truncating, disease-associated missense, and splicing mutations, abolish the function of the BRCA proteins. Germline BRCA mutations are usually heterozygous and cancer occurs through somatic loss/inactivation of the wild-type allele. Without a functional test or segregation with disease in a large affected family, it is difficult to determine if missense and noncoding variations cause disease.
Most genetic epidemiology studies have focused on white women with a strong family history of breast and/or ovarian cancer, although a few African-American families were included in the earliest studies. Pathogenic BRCA1 amino acid substitutions (missense mutations M1775R, C64G), which segregate with the disease in large African-American families and occur in functionally important regions of the protein, were first described in 199413, 19–21 (Table 1). BRCA1 protein-truncating, frameshift mutations have now been reported by multiple groups (Table 1).23, 24, 32 Three frameshift mutations were identified by Arena et al.23 in Florida African Americans with a strong family history of the disease, including a 10 base pair (bp) duplication (943ins10). Stoppa-Lyonnet et al.24 detected the same 10 bp duplication (943ins10) in one family who immigrated from the Ivory Coast. Gao et al.32 identified five protein-truncating BRCA1 mutations in nine high-risk families (56%). These BRCA1 mutations were identified in early-onset breast and/or ovarian cancer families whose affected females were younger than age 40 years at diagnosis. Four of the five BRCA1 mutations were also identified in families with three or more cases of breast and/or ovarian cancer. In a study of 85 African-American breast cancer patients, one additional BRCA1 frameshift mutation (1625del5) was identified by Gao et al.30
|BRCA1 mutations||Effect||No. Af ances fam||No. non-Af ances fam||References|
|155del4||FS||1 Af Am||0||22|
|943ins10||FS||7 Af Am, 1 Af||2||23–29|
|1625del5||FS||1 Af Am||0||30|
|1832del5||FS||2 Af Am||0||32|
|E673X||N||1 Af Am||0||26|
|2418delA||FS||2 Af Am||0||26|
|3331insG||FS||1 Af Am||0||33|
|3450del4||FS||1 Af Am||9||25, 26|
|3875delGTCT||FS||1 Af Am||35||26, 34|
|3883insA||FS||1 Af Am||0||32|
|3888delGA||FS||1 Af Am||0||23|
|K1290X||N||1 Af Am||1||26|
|4160delAG||FS||1 Af Am||0||23|
|Y1463X||N||1 Af Am||2||26|
|4730insG||FS||1 Af Am||0||26|
|4794insA||FS||1 Af Am||0||35|
|5296del4||FS||2 Af Am||9||26, 32|
|Disease associated missense mutations|
|C61G||MS||2 Af Am||65||36|
|C64G||MS||1 Af Am||2||20, 26|
|W1718C||MS||1 Af Am||1||26, 37|
|M1775R||MS||5 Af Am||7||13, 19, 26, 36|
|IVS4 − IG/T||S||1 Af Am||9||26, 35|
|IVS13 + IG/A||S||1 Af Am||0||26|
|IVS22 + 5G/T||S||1 Af Am||0||38|
|Unclassified variants and polymorphisms|
|K38K (G233A)||P||2 Af Am||2||26, 39|
|S186Y||UV||1 Af Am||2||26, 30|
|M2971||UV||1 Af Am||0||26|
|R315G||UV||1 Af Am||0||26|
|K355R||UV||1 Af Am||0||26, 40|
|Q356R (A1186G)||P||4 Af Am||90||26, 40|
|1379M||UV||3 Af Am, 1 Af||4||26, 31, 39|
|A521T||UV||1 Af Am||0||26|
|S616delS||1FD||1 Af Am||1||26|
|N723D||UV||1 Af Am||5||26|
|L771L (T2430C)||P||34 Af Am||159||26, 39|
|K820E||UV||9 Af Am, 1 Af||13||26, 31|
|P871L (C2731T)||P||1 Af Am||161||26, 40|
|P938P (A2933G)||P||2 Af Am||0||39|
|E1038G||P||34 Af Am||203||26, 39|
|S1040N||P||2 Af Am||21||26, 39|
|S1140G (A3537G)||P||14 Af Am||19||25, 26, 30, 32, 33, 39|
|K1183R (A3667G)||P||36 Af Am, 1 Af||186||25, 26, 31, 33, 39|
|Q1200H||UV||2 Af Am||0||26, 39|
|L1260L (T4932C)||P||4 Af Am||0||39, 40|
|S1297F (C4009T)||UV||1 Af Am||0||33|
|L1564P||UV||2 Af Am||1||25, 26|
|L1605L (T4932C)||P||2 Af Am||0||39|
|Q1785H||UV||1 Af Am||0||25|
|E1794D||UV||1 Af Am||0||25|
|IVS1 − 10T/C||UV||2 Af Am||0||26|
|IVS8 − 58delT||UV||36 Af Am||99||26, 39|
|IVS12 + 12delGT||P||2 Af Am||0||26, 39|
|IVS16 − ? 68G/A||P||34 Af Am||95||26, 39|
|IVS18 + ? A/G||P||34 Af Am||79||26, 39|
|IVS19 + 85delT||UV||1 Af Am||0||26|
|IVS20 + 59ins12||P||2 Af Am||33||26, 39|
|IVS22 + 7 T/C||UV||1 Af Am||0||25|
|IVS22 + 8 T/A||UV||1 Af Am||0||25|
|IVS22 + 8 T/C||P||7 Af Am||8||26, 34, 39|
|IVS22 + 67 T/C||P||5 Af Am||0||25, 34|
|IVS22 + 78 C/A||UV||2 Af Am||0||25|
|IVS23 − 10C/A||UV||1 Af Am||6||26|
|C5817G (3′UTR)||P||18 Af Am||4||26, 30|
Ganguly et al.35 reported two deleterious BRCA1 mutations among 10 African-American patients with a family history of breast cancer. Panguluri et al.25 identified two deleterious BRCA1 mutations (943ins 10 and 3450del4) among 45 high-risk African-American families treated at Howard University Hospital and selected for family history, early age of onset, breast and ovarian cancer, bilateral breast cancer, and male breast cancer. Shen et al.33 evaluated exons 2, 5, 11, 16, and 20 of the BRCA1 gene in 54 African-American breast cancer patients, not selected for family history or age, and found one novel frameshift mutation. Other mutations/variations in BRCA1 have been reported to the BIC26 by Myriad Genetic Laboratories and other investigators (Table 1).
In a population-based, case–control study in North Carolina, white women exhibited a higher frequency of BRCA1 mutations than African-American women.39 No disease-related BRCA1 mutations were identified in 88 African-American women with breast cancer, but three pathogenic BRCA1 mutations were identified in 120 white women with breast cancer. Family history and age of onset were not delineated by race for the cases. A polymorphism in the 3′ untranslated region of BRCA1, which is in linkage disequilibrium with a polymorphism in intron 22, was detected at a significantly higher frequency in African-American patients than in African-American controls.
Based on the observation of Gao et al.30 and Panguluri et al.25 the following observations are made in African-American women with at least two cases of female breast cancer or female breast and ovarian cancers among first-degree relatives. BRCA1 mutations were found in 4 of 39 (10%) families with breast cancer only (95% confidence interval [CI] = 3–25%), in 3 of 8 families (38%) with ovarian and breast cancers (95% CI = 10–74%), in 4 of 25 (16%) families with at least one breast cancer diagnosed before the age 50 and no ovarian cancer, (95% CI = 5–37%), and in 3 of 7 (43%) families with at least one breast cancer diagnosed before the age of 50 years and ovarian cancer diagnosed at any age (95% CI = 12–80%). The median age of diagnosis in BRCA1 carriers was 33.7 years (n = 7; range, 23–40 years), significantly different (P < 0.001, t test) from the median age of 49.3 years in noncarriers (n = 35, age range, 29–70).30, 41 These rates are comparable to those observed among whites.1, 15, 16, 42 Couch et al.1 reported that 7% (9 of 124) of multiple-case white families with breast cancer and no ovarian cancer had BRCA1 mutations whereas 40% (18 of 45) of families with breast and ovarian cancer had BRCA1 mutations. There was a significantly increased probability of identifying BRCA1 mutations when family members were diagnosed with breast cancer before the age of < 55 years. In primarily white women with breast cancer diagnosed before age 50 or ovarian cancer diagnosed at any age and in one first-degree or second-degree relative with either diagnosis, Frank et al.42 observed BRCA1 mutations at a comparable frequency of 18% (22 of 121) in families with breast cancer only and 35% (41 of 117) in families with breast and ovarian cancers.
Of the 26 distinct BRCA1 pathogenic mutations detected in African Americans or Africans, 58% (15 of 26) were previously unreported (Table 1). Twenty-three percent (6 of 26) of the pathogenic mutations have been detected in more than one family of African ancestry. However, only two mutations (M1775R and 943ins10) have been observed in more than two unrelated families. More than 500 mutations have been reported to the BIC and it is clear that African Americans exhibit a unique spectrum of deleterious BRCA1 mutations and variations in comparison to other ethnic groups.25, 30, 35 Large deletions in BRCA1 would not be detected by the techniques used in these studies.
The BRCA2 gene, with a coding region of more than 10,000 bp, has been less studied than BRCA1 in African Americans. A recurrent BRCA2 frameshift mutation, 2816insA, has been identified in African American families with breast and ovarian cancers and male breast cancer.30, 36, 43 Ganguly et al.35 reported three disease-related BRCA2 mutations among 10 African-American patients with a family history of breast cancer (Table 2). Four distinct disease-related BRCA2 mutations in African Americans have also been reported by Myriad.26
|BRCA2 mutations||Effect||No. Af ances fam||No. non-Af ances fam||References|
|1536del4||FS||1 Af Am||0||30|
|1882 del T||FS||1 Af Am||2||26, 41|
|1991delATAA||FS||1 Af Am||0||41, 43|
|1993delAA||FS||1 Af Am||0||41|
|2001delTTAT||FS||1 Af Am||0||43|
|2816insA||FS||2 Af Am||5||26, 30, 41, 43|
|3034del4 (3036del4)||FS||1 Af||35||26, 31|
|4075delGT||FS||1 Af Am||16||26, 41|
|4088delA||FS||1 Af Am||1||26, 41|
|6696delTC||FS||1 Af Am||2||26, 30|
|Q2342X||N||1 Af Am||0||26|
|7436del4||FS||1 Af Am||0||35|
|7795delCT||FS||2 Af Am||0||26, 30|
|7907delTT||FS||1 Af Am||0||35|
|8643 delAT||FS||1 Af Am||0||41|
|9481insA||FS||2 Af Am||2||26|
|R3128X||N||1 Af Am||7||26|
|IVS13 − 2A/G||S||1 Af Am||0||35|
|Unclassified variants and polymorphisms|
|P46S||UV||1 Af Am||0||26|
|P59A||UV||1 Af Am||0||26|
|N108H||P*||1 Af Am||1||26, 30|
|Q147H||UV||1 Af Am||0||26|
|A248T||UV||1 Af||1||26, 31|
|N289H||P*||1 Af||11||26, 31|
|Q713L||UV||1 Af Am||0||26|
|L929S||UV||1 Af Am, 2 Af||6||26, 31|
|S976I||UV||1 Af Am||3||26|
|N987I||UV||1 Af Am, 2 Af||6||26, 31|
|N991D||P*||1 Af||9||26, 31|
|S1172L||UV||2 Af Am||4||26|
|C1290Y||P*||1 Af Am||2||26|
|Q1396R||UV||1 Af Am||8||26|
|T1414M||P*||1 Af||4||26, 31|
|D1420Y||P||1 Af Am||113||26|
|D1781G||UV||1 Af Am||0||26|
|N1880K||P*||4 Af Am||4||26|
|T1980I||UV||1 Af Am||0||26|
|H2074N||P*||2 Af Am||2||26|
|H2116R||UV||2 Af Am||7||26|
|K2339N||UV||4 Af Am||8||26, 30|
|Q2384K||UV||1 Af, 1 Af Am||7||26, 30, 31|
|H2440R||UV||6 Af Am||9||26, 30|
|A2466V||P*||8 Af Am||24||26|
|S2835P||UV||1 Af Am||2||26|
|I2944F||P*||9 Af Am||6||26|
|S3020C||UV||1 Af Am||0||26|
|M3118T||UV||1 Af Am||0||26|
|G3212R||UV||1 Af Am, 2 Af||0||26, 31|
|V3244I||UV||3 Af Am||8||26|
|T3357I||UV||1 Af Am||0||26|
|I3412V||P||15 Af Am||74||26|
|IVS6 − 19 C > T||UV||2 Af Am, 2 Af||9||26, 31|
|IVS11 + 73 T > A||P*||1 Af||0||31|
|IVS18 + 109 G > A||UV||2 Af||0||31|
|IVS20 − 36 C > G||UV||1 Af||0||31|
|IVS24 − T||UV||1 Af||0||31|
|IVS26 + 10 T > G||UV||1 Af Am||0||26|
|IVS26 + 106 delT||P*||1 Af Am||0||26, 31|
In a study of 74 high-risk African-American breast cancer patients treated at Howard University Hospital and selected for family history as described above, Kanaan et al.41 and Whitfield-Broome et al.43 identified 8 of 74 (11%) pathogenic, BRCA2 frameshift mutations after examination of the entire coding and flanking sequences (Table 2). Numerous polymorphisms and noncoding variants were also observed in the BRCA2 gene. Fifty percent of the pathogenic mutations were novel and possibly unique to African Americans and one-half were observed in women younger than the age of 40 years, with a family history of breast or ovarian cancer or other cancers. Two pathogenic mutation carriers were males. In the population based case–control study in North Carolina, white women exhibited a three times higher frequency of BRCA2 mutations than African-American women.45 One disease-related BRCA2 mutation was identified in 88 African-American women with breast cancer. In a worldwide study of 71 breast cancer families and 95 controls, Wagner et al.44 did not identify any deleterious BRCA2 mutations in African-American or African families. Consistent with the greater genetic diversity observed in people of African ancestry, a higher frequency of sequence variations was found in Africans than in other worldwide populations.
After combining the BRCA2 data of Gao et al.30 and Kanaan et al.,41 the following observations were made in African-American women with at least two cases of breast or breast and ovarian cancers among first-degree relatives. BRCA2 mutations were found in 3 of 54 families (6%) with breast cancer only, in 4 of 12 families (33%) with ovarian and breast cancers, in 3 of 35 families (9%) with at least one breast cancer diagnosed before the age 50 and no ovarian cancer, and in 2 of 10 families (20%) with at least one breast cancer diagnosed before the age 50 and ovarian cancer diagnosed at any age. In primarily white women with breast cancer diagnosed before age 50 or ovarian cancer diagnoses at any age and one first- or second-degree relative with either diagnosis, Frank et al.42 observed BRCA2 mutations at a similar frequency of 11% (13 of 121) in families with breast cancer only and 15% (18 of 117) in families with breast and ovarian cancers. Among white families, BRCA1 mutations are far more common than BRCA2 mutations in families with breast and ovarian cancers; whereas, BRCA2 mutations account for a higher proportion in male breast cancer and in families with female breast cancer only, depending on the number of cases.15, 42
In our African-American cohort, the median age of diagnosis of breast cancer among BRCA2 carriers was 44.4 years (n = 7, age range, 34–58 years), not significantly different from 48.3 years in noncarriers (n = 51, age range, 29–70 years).30, 41 Among white families with four or more cases of breast cancer or breast and ovarian cancers, the median age of diagnosis of female breast cancer among BRCA2 carriers was 45.1 years, similar to that observed in African Americans.16 African-American BRCA2 mutation carriers develop cancer at a significantly later age of onset than BRCA1 mutation carriers (P < 0.05), as has been described for whites.15, 16, 42
Of the 18 distinct pathogenic BRCA2 mutations detected in families of African ancestry, 56% (10 of 18) are novel and probably unique to this group (Table 2). Seventeen percent (3 of 18) of the pathogenic mutations have been detected in more than one African-American or African family. No BRCA2 mutations were carried by more than two families of African ancestry. This distribution of African-American BRCA2 mutations is very similar to that for BRCA1. Likewise, most of the distinct BRCA1 and BRCA2 mutations reported in the BIC (frequency graphs) occur in only a few families.26 Numerous BRCA1 and BRCA2 polymorphisms and missense and noncoding variants are observed in African Americans (Tables 1, 2). Large deletions in BRCA2 would not be detected by the techniques used in these studies.
Breast cancer is rare in populations indigenous to the African tropics, predominantly afflicting young women.46 However, the International Agency of Research on Cancer Bulletins and Surveys in seven African countries has reported that breast cancer incidence has increased from 15.3 per 100,000 in 1976 to 33.6 per 100,000 in 1998.46 Incident female breast cancer rates for whites and African Americans in the United States are 113.2 and 99.3 per 100,000, respectively.47 The rising incidence in Africa has been attributed to increased reporting and the adoption of a Western lifestyle in urban cities. In a recent review of breast cancer cases from the University of Ibadan. Nigeria, the average age at diagnosis was 42.6 years, 10–15 years younger than in whites.48 The young average age at diagnosis could be partly explained by the low mean age of the general African population. However, multiple studies in the United States have also documented a higher breast cancer incidence and death rate in premenopausal African-American women compared with non-Hispanic whites (http://www-seer.ims.nci.nih.gov). It is likely that the shared genetic background of Africans and U.S. African Americans contributes to the greater susceptibility to early-onset breast cancer in both groups but this has not been evaluated carefully. In the first study of its kind, the entire coding regions and the intron/exon boundaries of BRCA1 and BRCA2 have been evaluated in 70 African breast cancer patients younger than 40 years of age.31 These patients were ascertained at the University of Ibadan College of Medicine, Nigeria, and were not selected for a family history of breast cancer. In this cohort, two BRCA1 truncating mutations, four BRCA1 missense variations, one BRCA2 truncating mutation, and nine different BRCA2 missense variations were identified (Tables 1, 2). The truncating BRCA1 mutation, Q1090X, has never been described before and was not seen outside of one family identified in this cohort. The 1742insG mutation is also unique to this cohort. The BRCA1 amino acid substitution alleles, however, have all been described in other population. For example, alleles E1038G and K1183R have both been described as benign polymorphisms and I379M and K820E have both been described as unclassified variants.26 The BRCA2 truncating mutation, 3034del4, has been described as a mutational hotspot.49 The BRCA2 missense variation, N1880R, has never been reported. The BRCA2 alleles, G3212R, A248T, N987I, and L929S, have all been reported independently and are listed as unclassified variants.26
When the same mutation is found in multiple unrelated families, this may be due to ancestry from a small isolated group of founders or to independent mutational events. A common haplotype among unrelated families around the gene of interest is evidence of a founder effect. The length of the common haplotype is inversely related to the age of the mutation. The BRCA1 943ins10 mutation was associated with a single haplotype in five families from the Ivory Coast, Washington DC, Florida, South Carolina, and the Bahamas.27 The length of the common haplotype is about the same as the length of the Ashkenazi Jewish founder mutation, 185delAG, which has been estimated to be 760 years old.50 Therefore, the BRCA1 943ins10 mutation is an ancient founder mutation of West African origin. A common haplotype was reported for two African-American families with the BRCA1 5296del4 mutation and for two African-American families with the BRCA1 1832del5 mutation.32 As shown in Tables 1 and 2, BRCA mutations detected in African Americans or Africans have also been reported multiple times in families with and without African ancestry, but haplotype analysis is needed to determine if they represent founder mutations unique to African Americans. Due to the higher level of variations/polymorphisms among African Americans compared with whites, wide geographic origins in Africa and genetic admixture, recurrent mutations are likely to be more widely dispersed in the African diaspora and therefore not readily identifiable.25, 30, 35, 41 Genetic testing in African Americans would have to include complete sequencing of both BRCA1 and BRCA2 genes.
Little information exists about other familial cancer syndromes unique to African Americans, but two African-American families with Cowden syndrome have been reported.51 The same germline p53 coding mutation and haplotype were detected in two Li-Fraumeni African-American families, one of which exhibited primarily breast and ovarian cancer.52
Pregenetic and postgenetic counseling is extremely important for genetic testing. Genetic counseling translates basic scientific advances into a practical and understandable form of information for the patient. It involves the collection of medical and family information, recognition of familial syndromes based on pedigree analysis, calculation of risk estimates, and effective communication of risk status at a level that the patient can understand. The National Society of Genetic Counselors has developed guidelines that counselors should follow.53, 54 These include respect for the autonomy and privacy of the individual, the need for confidentiality and informed consent, and the provision of information to the patient in a nondirective manner.55, 56 Most importantly, the patient should be educated about cancer prevention practices. As cancer risk assessment moves from the research setting into clinical practice, genetic counseling and patient education must be an integral part of such programs.
White women from socioeconomically advantaged circumstances comprise the majority of clients who use genetic counseling and testing options even when covered by third-party payers.57, 58 It has long been recognized that minority and economically disadvantaged patients do not participate in clinical trials.59 This situation has been attributed to a number of reasons including ignorance of the availability, fear and distrust, perception of cost, access and transportation, manner of information presentation, lack of valid, culturally sensitive questionnaires, and the language of consent forms.60, 61 Although data are limited, anecdotal reports suggest that minorities are also less likely to use cancer genetics services unless a major outreach effort is directed toward their inclusion. The University of Chicago Cancer Risk Clinic has made a major commitment to provide avenues for women of all socioeconomic backgrounds to take advantage of recent advances in cancer genetics, including genetic testing, precounseling, and postcounseling.30, 32, 42, 62 In a report on the African American Hereditary Prostate Cancer (AAHPC) Study, an ongoing multicenter genetic linkage study organized by investigators at Howard University and the National Human Genome Research Institute in collaboration with a consortium of predominantly African-American urologists, Royal et al.63 found that physician referral and tumor registries were by far the most productive recruitment mechanism. The challenges and successes of the recruitment experience described in the first phase of the AAHPC study should inform future efforts to involve this population in similar studies.
BRCA mutations are rare in the general population. Therefore, genetic testing should be recommended in the context of a comprehensive cancer risk assessment. There is no reason to suspect that the expression of BRCA mutations in African-American families with breast and ovarian cancers is different than the expression in white families. Therefore, general guidelines that have been published by other professional groups should be followed. The American Society for Clinical Oncology recommends that genetic testing should be considered when there is at least a 10% probability of detecting a deleterious mutation. Genetic counseling and testing should probably be offered to patients with early-onset disease (younger than age 35 years) and to multicase families in which at least one breast cancer was diagnosed before the age 50 years or ovarian cancer diagnosed at any age. Families with at least one male breast cancer are also candidates for testing. Genetic testing could provide valuable information because BRCA carriers with breast cancer have a 10-fold elevated risk of developing ovarian cancer and are at an increased risk of developing contralateral breast cancer, compared with noncarriers.42 Bilateral prophylactic oophorectomy in BRCA carriers reduces the risk of breast and ovarian cancers.64, 65 We should intensify efforts to integrate genetic counseling and testing into the clinical care of young African-American women already affected by cancer. Identification of deleterious mutations in index breast cancer cases could provide the link to other at-risk family members. Access to genetic testing may help minority women from high-risk families develop better strategies to reduce their risk of dying of breast or ovarian cancer. However the complexities of genetic testing including the unresolved psychosocial issues warrant more research.
The University of Chicago Cancer Risk Clinic conducted three focus group sessions to evaluate the informational needs of African Americans participating in genetic testing trials. Most participants believed that the African-American culture offers a unique perspective on genetic testing. The collective history of African Americans provides a set of issues related to cancer prevention, treatment, and medical research in general that is distinct from Euro–American issues. At the same time, participants acknowledged the universality of the human experience with cancer and the desire to be treated like everyone else.
Conclusions and recommendations from the focus group studies include
An intensive outreach program focused on cancer control through genetics could improve awareness of genetics in the African-American community. Compared with white women, African-American women had lower levels of knowledge and had more positive attitudes about the benefits of genetic testing.66 There were no significant ethnic differences in attitudes about the limitations and risks of testing. However, income was negatively associated with this outcome. Ethnic differences in knowledge and attitudes about genetic testing for breast ovarian cancer risk may be attributable to differences in exposure to genetic information and referral by health care providers.
Little information exists about the rates or predictors of test use among African Americans. In the few studies that have evaluated rates of test use among individuals from high-risk families who have self-referred for genetic counseling/testing, spiritual faith and psychologic factors influenced testing decisions. Schwartz et al.67 published their findings on 290 (including African-American) women with familial breast cancer who were offered genetic counseling and testing for alterations in the BRCA1 and BRCA2 genes.
Baseline levels of spiritual faith, cancer-specific distress, perceived risk, and demographic factors were evaluated to identify independent predictors of whether participants received versus declined testing. Among women who perceived themselves to be at low risk of developing breast cancer again, those with higher levels of spiritual faith were significantly less likely to be tested, compared with those with lower levels of faith (OR, 0.2; 95% CIs, 0.1 and 0.5). However, among women with high levels of perceived risk, rates of test use were high, regardless of levels of spiritual faith (OR, 1.2; 95% CIs, 0.4 and 3.0). These results highlight the role that spirituality may play in the decision-making process about genetic testing. Unfortunately, in our experience, we have found that African-American women generally underestimate their risk and this correlated with higher levels of spiritual faith. In fact, despite extensive genetic counseling, cancer risk perception among African-American women remains closely associated with personal experiences.68 Consideration of these factors may be important in effectively designing risk assessment and education programs for minority women.
When compared with non-Hispanic white women, little data exist about the contribution of BRCA1 and BRCA2 mutations to breast cancer in African-American and African families. Although a number of unique mutations have been described, recurrent mutations are widely dispersed and are not readily identifiable in the few families that have been tested. Broad generalizations cannot be made based on the few families that have been tested, but the probability of finding a mutation is invariably dependent on the age at diagnosis and the number of breast and/or ovarian cancer cases in the family. More resources should be available for establishing a large cohort of African-American and African families, defining prevalence and the mutation spectrum in BRCA1 and BRCA2 genes, and evaluating gene-gene a nd gene-environment interactions that contribute to breast cancer in these families. Access to genetic counseling and testing in a culturally sensitive research setting must remain a high priority before genetic testing can be disseminated in the community.