Prevalence of the four common BRCA1 and BRCA2 founder mutations in Colombian breast patients of African descent

Breast cancer is a major cause of morbidity and mortality as it is the most common invasive cancer in women worldwide, accounting for 20% of all malignancies. Inherited mutations in the BRCA1 and BRCA2 genes are the strongest genetic predictors of breast cancer and are the primary causes of familial breast and breast-ovarian cancer syndromes. Germline mutations in the BRCA1 and BRCA2 genes confer high lifetime risks of breast and ovarian cancer. The average magnitude of the cumulative risk varies within and between families, which may depend on racial/ethnic differences in genetic, reproductive or environmental exposures as well as other factors (Kurian, 2010). The frequency, spectrum and penetrance of mutations in the BRCA1/2 genes have been determined in several Caucasian, Asian and few Hispanic populations. Little is known about the contribution of BRCA1/2 to hereditary breast cancer in African and African-American populations. These populations suffer from a disproportionate burden of early-onset disease, with aggressive tumour features, such as high frequency of hormone receptor-negative tumours, comparatively high frequencies of medullary or atypical medullary carcinoma, poor differentiation, aneuploidy, p53 mutations and higher mortality rates. These features are in many ways similar to those of BRCA1-associated breast cancers (Armes et al. 1999; Fackenthal et al. 2012). There is certainly an association between race/ethnicity and cancer. In fact, distinctive cancer patterns have been identified for various racial/ethnic groups. Breast cancer tends to appear in black women at a younger age and in more advanced forms. Black women are also two times more likely to develop triple-negative breast cancer, an aggressive subtype of the disease which has only few effective treatment options. Triple-negative breast cancers tend to grow and spread more quickly than most other types of breast cancer. These tumours are known to be associated with higher breast density compared to non-triple negative tumours. Breast density is one of the strongest predictors of breast cancer risk and is also a known factor limiting the sensitivity of a screening mammogram. Mammograms of breasts with high density have been described as harder to read and interpret than those of less dense breasts. A small cancer can be concealed by dense breast tissue or by the overlap of normal breast structures (Domchek et al. 2006). The contribution of BRCA1/2 germline mutations to hereditary breast/ovarian cancer has been poorly investigated in minority populations, such as African-Americans from South America. The term ¿Afro-Colombians¿ refers to Colombians of African ancestry. Historical evidence suggests a complex genetic structure of the Colombian population, which settled as a result of a strong miscegenation between Europeans (mainly men from Spain and Portugal) and native women and to a less extent between Europeans and Africans who came to the Americas as slaves, mainly from Guinea, Congo, Angola and Mozambique (Salzano et al. 2002). Enslaved Africans first were imported into Colombia by the Spaniards in the first decade of the 16th century. Upon arrival, the Africans started replacing the rapidly declining native American population. During the slave trade, Colombia was a major destination for slave ships. Towns like Cartagena de Indias were some of the most important ports through which enslaved Africans entered to Colombia and Panama, as well as parts of Ecuador, Peru, Brazil, Costa Rica, Venezuela and Nicaragua. From here, the slaves were sold and moved to various destinations in the Andes and beyond. After the abolition of slavery in 1851, the Colombian Government promoted the ideology of ¿mestizaje¿, meaning the mixing of African and indigenous people with white Spaniards and their descendants. By the 1970s many black people had migrated to the cities in search of new opportunities. In cities like Bogota, they became the urban poor, living in marginal areas. It has been estimated that only a limited number of Afro-Colombians recognise their own black ancestry, while most of them do not, as a result of the difficult inter-racial relationships with white and indigenous Colombians. Today, the population of black people mainly settled around the Pacific and Atlantic coasts comprises 36-40% of the national population, although the official percentage given by the 2005 population census was 10.6% (http://www.dane.gov.co/files/censo2005/ etnia/sys/Afro_indicadores_sociodemograficos_censo2005.pdf). After Brazil, Colombia has the largest population of African descent in Latin America (The African Diaspora in Colombia, http://www.thepatriot.co.zw/?p=3670). Both recurrent and population-specific BRCA1/2 mutations have been identified in populations of African ancestry with high frequency variations. Fackenthal and colleagues performed a complete BRCA1/2 sequence analysis of 434 breast cancer cases from Nigeria. In contrast to previously reported low BRCA1/2 mutation frequencies in African-American populations, he and his colleagues found an exceptionally high frequency of BRCA1 (7.1%) and BRCA2 (3.9%) mutations in Nigerian breast cancer patients unselected for age of onset or family history (Fackenthal et al. 2012). Immediately after the identification of the twelve recurrent BRCA1/2 mutations (BRCA1: Y101X, 1742insG, 4241delTG, M1775R, 4359insC, C64Y, 1623delTTAAA, Q1090X, 943ins10; BRCA2: 1538delAAGA, 2630del11, 9045delGAAA) in the Nigerian study, a replication cohort of 356 Nigerian, African-American and Barbadian (African ancestry) breast cancer patients was screened for these mutations. Of the twelve recurrent mutations, six were identified in eleven patients in the replication study (3.1%) (Zhang et al. 2012). Other reports showed lower frequencies of BRCA1 and BRCA2 mutations in African-Americans. One study conducted among 1,628 population-based black breast cancer cases selected for family history or age of onset reported mutation frequencies of 1.4% in BRCA1 and 2.6% in BRCA2 (Malone et al. 2006). In a comparative analysis of ethnically diverse families (white, Ashkenazi Jewish, African-American, Hispanic, Asian) with two or more cases of breast and/or ovarian cancer among first- and second-degree relatives, deleterious BRCA1/2 mutations occurred at a lower mutation frequency in African-Americans compared to non-Hispanic, non-Jewish whites (27.9% vs 46.2%) and were highest for Askhenazi Jewish families (69%) (Nanda et al. 2005). Surprisingly, only two founder mutations have been identified in African-Americans: 943ins10 and IVS13+1G>A in BRCA1 (Pal et al. 2004).