Seventeen years after BRCA1: what is the BRCA mutation status of the breast cancer patients in Africa? – a systematic review

Epidemiology of breast cancer

Breast cancer is the most common malignancy affecting women worldwide. According to GLOBOCAN there were 1.38 million new cases of breast cancer in the world in 2008, with a corresponding mortality of 458,000. In Africa, over the same time period, there were 68,000 new cases with 37,000 deaths documented, although this probably represents a gross underestimation due to incomplete case ascertainment and reporting Adesunkanmi et al. (2006). In 2010, the World Health Organisation (WHO) estimated that there would be 97,743 new breast cancer cases in Africa, with an estimated mortality of 52,855 IARC (2011).

The reportedly lower incidence of breast cancer in Africa may be explained by lower life expectancy, incomplete record keeping and paucity of epidemiological studies and incomplete case ascertainment. In addition, peculiarities in the presentation of breast cancer in Africa may limit detection Adesunkanmi et al. (2006). These include an apparently younger age and later stage at presentation with more aggressive tumour characteristics Adesunkanmi et al. (2006). The late presentation which may be a consequence of poor health seeking behaviour is also compounded by the more aggressive nature of breast cancer in Africa.

The cause(s) of breast cancer remain largely unknown, though several risk factors have been characterised. The most important factors are the age of the patient and the effect of female sex hormones. Thus early menarche, late menopause and nulliparity all confer an increased risk of breast cancer. Breast feeding is noted to be protective while ingestion of exogenous female sex hormones is a risk factor for breast cancer.

A positive family history of breast cancer is known to increase the risk of breast cancer. However, it was only in 1990, based on the results of linkage analysis performed by Hall et al. (1990) that firm evidence was provided for the existence of at least one hereditary breast cancer gene. Miki et al described the first germ line mutation known to confer increased risk of breast cancer in 1994, labelled BRCA1 Miki et al. (1994). Shortly thereafter, a second germ line mutation associated with increased risk was also identified and named BRCA2 Wooster et al. 1995). Subsequently, several susceptibility genes have been associated with breast cancer. These genes confer ‘high-risk’ and ‘low to moderate risk’ of breast cancer. The high-risk breast cancer susceptibility genes include BRCA1, BRCA2, PTEN, TP53, LKB1/STK11 and CDH1, with relative lifetime risks higher than 4 (but generally much higher at young ages). The CHEK2, TGFβ1, CASP8 and ATM genes belong to the ‘low to moderate-risk’ breast cancer susceptibility genes Oldenburg et al. (2007).

BRCA1 mutation carriers have a 30% risk of developing ovarian cancer during their lifetime Whittemore et al. (1997) and a 50–80% risk of developing breast cancer before the age of 70 years Deng (2006). BRCA1 is mapped to chromosome 17q21 Adesunkanmi et al. (2006); it contains 24 exons and encodes a protein of 220 kDa, composed of 1863 amino acids Chen et al. (1996). The second breast cancer susceptibility gene, BRCA2, is localized on the long arm of chromosome 13. BRCA2 is also a large gene, with 27 exons that encode a protein of 380 kDa, composed of 3418 amino acids Bertwistle et al. (1997).

Risk-associated truncation mutations are found throughout the entire BRCA1 coding sequence Linger & Kruk (2010). The majority of risk-associated mutations are frameshift or nonsense mutations that result in a premature stop codon and truncated protein product (NIH Breast Cancer Information Core Database, http://research.nhgri.nih.gov/bic/). Both BRCA1 and BRCA2 are thought to act as classical tumour suppressor genes and the loss of their cellular functions is thought to occur through bi-allelic inactivation. Carriers of mutations have one germline hit (the inherited mutated copy of BRCA1) and, in the tumour, a second somatic hit usually through the loss of heterozygosity Deng (2006; Collins et al. 1995).

A determination of BRCA genetic mutational status will go a long way towards advice on prophylaxis for breast cancer. The data on BRCA gene mutations in Africans is sparse. The mutational spectrum of BRCA1/2 in African Americans has not been as well characterized as that of Caucasians Ferla et al. (2007).

The knowledge base about the various genetic mutations in the BRCA genes of people of African origin is scattered in diverse small pockets of articles. The aim of this study is to collate all these data and present them in a single review in order to better characterise the genetic mutational spectrum of the indigenous African people.

BRCA1 and BRCA 2 mutations

North African (NA)

Balci et al. (1999) evaluated BRCA1 and BRCA2 in Turkish breast and ovarian cancer patients with a strong family history of breast cancer in 1999. The whole of the genes were evaluated. In this group of 15 Families of 33 patients, three deleterious mutations (2 BRCA1 and 1 BRCA2) were detected. The BRCA2 mutation was detected in one of the male breast cancer patients.

Ozdag et al. (2000) in 2000 published a study on 50 high risk Turkish Breast cancer patients. Patients were selected based on four criteria; early age at onset, male breast cancer, hereditary breast cancer and familial breast cancer. Exons 2, 5, 11 (10 overlapping fragments), 13, 20 & 24 of BRCA1, and exon 11 (7 overlapping fragments) of BRCA2 were analysed. Four deleterious mutations were found. There were 2 (BRCA2) mutations in the patients with hereditary breast cancer. The other 2 (BRCA1) mutations were found in patients with early onset breast cancer. One of these patients had 2 mutant alleles. There was no truncating mutation discovered in the male breast cancer group. There were 5 BRCA1 sequence variants detected in 23 other patients.

In another Turkish study, Yazici et al. (2000) found 8 BRCA1 and 2 BRCA2 mutations in 11 out of a cohort of 105 patients with breast or ovarian cancer. One (1) of the mutations was found only in an ovarian cancer patient and will not be part of the summary. Half of the patients had a family history while the remaining half had early onset breast cancer (< 50 years). Their analysis was initially limited to exon 11 of both genes and exon 10 of BRCA2. They also performed complete analysis of the BRCA1 gene in a subset of 24 patients and found further mutations in exons 14 and 20, one of which was the Askenazi Jewish mutation 5382insC. This led them to do a heteroduplex analysis of exons 2, 14 and 20 of the BRCA1 gene in all the patients. There was a higher incidence of BRCA mutations (7 BRCA1 and 1 BRCA2) in patients with a family history. Five truncating mutations were identified in exon 11 of both genes. The remaining mutations were in exon 2, 14, 20 and intron 14.

Uhrhammer et al. (2008) performed a study to determine the contribution of BRCA1 mutations to breast cancer in Algeria. The patient population (64) was selected on account of a family history of Breast cancer (13) and early onset Breast cancer (51) (< 38 yrs). They evaluated the whole of the BRCA1 gene. A total of 7 deleterious mutations were found in 11 patients representing 9 families. One of these mutations was found in a patient with early onset breast cancer and another patient with familial breast cancer. Another mutation was found in 2 different families with familial breast cancer.

Troudi et al. (2007) in Tunisia studied 36 patients with family history of breast or ovarian cancer. All of the BRCA1 and BRCA2 genes were analyzed. They found 6 deleterious mutations in 7 patients. Four of these were in BRCA1 (5 patients) and the remainder were in BRCA2 (2 patients). In addition to these mutations, nine distinct unclassified sequence variants (8 in BRCA1 and 1 in BRCA2) and 16 distinct polymorphisms (12 in BRCA1 and 4 in BRCA2) were identified.

Cherbal et al. (2010) studied 86 high risk individuals – male breast cancer, strong family history of breast, ovarian and/or prostate cancers – from 70 families. All the regions of the BRCA1 and BRCA2 genes were evaluated for mutations. Individuals were screened by High-Resolution Melting (HRM) curve analysis followed by direct sequencing. Samples for which no pathogenic mutation was found were analyzed by MLPA. Three pathogenic mutations in BRCA 1 gene and two within BRCA2 gene were detected using PCR and HRM. Using MLPA, a novel deletion of BRCA1 exon 2 and a deletion of BRCA1 exon 8 were identified in two patients with breast/ovarian cancer and bilateral breast cancer, respectively. The mutations occurred in 8 of 70 families.

Mahfoudh et al. (2011) studied 24 patients in 16 breast/ovarian cancer families. All the coding regions of the BRCA1 gene were analysed. Six families had four deleterious mutations one of which (IVS5 + 2insG) was novel. Another of the mutations (916delTT) was noted in 3 apparently unrelated families.