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.