Several recent studies have demonstrated the unique clinical and biological behaviour of breast cancers in African American women.17,21,26
The weight of evidence clearly demonstrates more aggressive biological behaviour as well as an earlier onset of disease in this group. A recent study by Jones et al
demonstrated a higher incidence of somatic p53 mutations in primary tumour specimens from African American breast cancer patients.23
Several studies have evaluated other biological differences in breast cancer in African American women, which were summarised in a recent editorial by Newman, who concluded that “the door to the improved understanding of ethnicity related variation in breast carcinoma risk and outcome has now been wedged open by the powerful tools of molecular oncology”.27
The development of YBC is a common problem with substantial clinical, epidemiological, social, and psychological implications. The relatively recent identification of the BRCA1 and BRCA2 genes has contributed substantially to our understanding of the contribution of these genes to familial breast cancer.28,29,30
Although BRCA1 and BRCA2 mutations have been extensively studied in some populations, the frequency of mutations in African American populations has not.24,31,32,33,34,35
Furthermore, most studies evaluating BRCA1/2 mutations tested highly selected populations with strong family histories or with suspected genetic predisposition to breast cancer. It is therefore difficult to assess the contribution of mutations to the general problem of breast cancer diagnosed at a young age from these highly selected populations.
In the current study we did not select patients based on family history or genetic predisposition. These patients were recruited from our database of patients seen in the Department of Therapeutic Radiology for early stage, early onset breast cancer. Although selection biases are always a potential issue, it should be noted that the distribution of African American and white patients in this study did not significantly differ from that in our database. Specifically, we recruited 30 of 71 African American women in the database (42%) compared to 170 of 423 white women (40%). Therefore, our sample is representative of the overall population. Furthermore, there were no significant differences between the African American and white populations with respect to family history, which provides additional evidence that the sample was not biased regarding familial predisposition.
One notable finding from our study is that the frequency of known deleterious mutations in the young African American population did not significantly differ from that of the white population. While larger population studies are clearly indicated, these data do not suggest that a higher frequency of deleterious mutations accounts for the younger age of onset of breast cancer in African American women. However, the relative distributions of mutations did differ, with most African American women having mutations in BRCA2 compared to BRCA1. A recent study by Gao et al
also reported a higher frequency of BRCA2 mutations compared to BRCA1 mutations in African American breast cancer families.24
In that study, four of five deleterious mutations and four of six missense variants were BRCA2. However, in another recent study in 10 African American families, Pal et al
observed deleterious mutations in BRCA1 in two families and BRCA2 in two families.35
While complete sequencing of both genes remains the standard, these results could have some implications with respect to the priority of which gene to sequence first in African American women.
Another significant finding from the current study is the high frequency of variants of uncertain significance in the African American population. It is difficult to determine what, if any, contribution these variants make to the development of breast cancer in these young women. The table summarising all the variants (table 4), as well as our analysis of family history and other cancers developing in individuals with variants of uncertain significance, however, suggest that many of these variants may not be associated with disease risk. In fact, the phenotype of the variants of uncertain significance was much more consistent with the wild type phenotype than with those of the deleterious mutations in our selected population. Another study by Fackenthal et al
also observed a higher frequency of BRCA2 variants of uncertain significance in a cohort of young Nigerian breast cancer patients.36
Of 39 patients, 74% had variants of uncertain significance in BRCA1 or BRCA2.
The possibility that deleterious mutations or variants of uncertain significance in BRCA1 or BRCA2 contribute to the earlier onset of breast cancer in African American women can not be confirmed or excluded from the data presented here. Larger, well designed population based studies will be required to determine the significance of these changes in the BRCA1 and BRCA2 gene in the earlier onset of breast cancer in these populations. The relatively high rate of variants and deleterious mutations in these young African American women, however, clearly warrants further investigation. With increasing numbers of women identified with these variants of uncertain significance, we will be able to better determine their clinical implications and use such data to appropriately counsel patients and their families.
We conclude that African American women with early onset breast cancer have a unique spectrum of mutations in BRCA1/2. The incidence of deleterious mutations in this population of young African American women with breast cancer did not differ significantly from that in young white women. However, more of the deleterious mutations appear to be in the BRCA2 gene. The frequency of variants of uncertain significance in the African American population also appears to be higher. However, correlation of these variants of uncertain significance with clinical indicators, including a strong family history of breast and/or ovarian cancer and the development of second malignancies, indicates that patients with these variants appear to be phenotypically similar to sporadic (wild type) patients in this selected population. Review of the literature and available data on these variants also suggests that these variants are less likely to be related to disease risk. However, further studies are clearly warranted to determine the clinical significance and implications of these variants of uncertain significance among all populations. Such data will further contribute to our understanding of the clinical implications of genetic changes in the BRCA1 and BRCA2 genes and aid in the counselling process.